Journal articles: 'Ataxia Telangiectasia and Rad3-related (ATR)'

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Friesner, Joanna D., Bo Liu, Kevin Culligan, and Anne B. Britt. "Ionizing Radiation–dependent γ-H2AX Focus Formation Requires Ataxia Telangiectasia Mutated and Ataxia Telangiectasia Mutated and Rad3-related." Molecular Biology of the Cell 16, no. 5 (May 2005): 2566–76. http://dx.doi.org/10.1091/mbc.e04-10-0890.

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The histone variant H2AX is rapidly phosphorylated at the sites of DNA double-strand breaks (DSBs). This phosphorylated H2AX (γ-H2AX) is involved in the retention of repair and signaling factor complexes at sites of DNA damage. The dependency of this phosphorylation on the various PI3K-related protein kinases (in mammals, ataxia telangiectasia mutated and Rad3-related [ATR], ataxia telangiectasia mutated [ATM], and DNA-PKCs) has been a subject of debate; it has been suggested that ATM is required for the induction of foci at DSBs, whereas ATR is involved in the recognition of stalled replication forks. In this study, using Arabidopsis as a model system, we investigated the ATR and ATM dependency of the formation of γ-H2AX foci in M-phase cells exposed to ionizing radiation (IR). We find that although the majority of these foci are ATM-dependent, ∼10% of IR-induced γ-H2AX foci require, instead, functional ATR. This indicates that even in the absence of DNA replication, a distinct subset of IR-induced damage is recognized by ATR. In addition, we find that in plants, γ-H2AX foci are induced at only one-third the rate observed in yeasts and mammals. This result may partly account for the relatively high radioresistance of plants versus yeast and mammals.

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Kumbhar, Ramhari, Sophie Vidal-Eychenié, Dimitrios-Georgios Kontopoulos, Marion Larroque, Christian Larroque, Jihane Basbous, Sofia Kossida, Cyril Ribeyre, and Angelos Constantinou. "Recruitment of ubiquitin-activating enzyme UBA1 to DNA by poly(ADP-ribose) promotes ATR signalling." Life Science Alliance 1, no. 3 (June 2018): e201800096. http://dx.doi.org/10.26508/lsa.201800096.

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The DNA damage response (DDR) ensures cellular adaptation to genotoxic insults. In the crowded environment of the nucleus, the assembly of productive DDR complexes requires multiple protein modifications. How the apical E1 ubiquitin activation enzyme UBA1 integrates spatially and temporally in the DDR remains elusive. Using a human cell-free system, we show that poly(ADP-ribose) polymerase 1 promotes the recruitment of UBA1 to DNA. We find that the association of UBA1 with poly(ADP-ribosyl)ated protein–DNA complexes is necessary for the phosphorylation replication protein A and checkpoint kinase 1 by the serine/threonine protein kinase ataxia-telangiectasia and RAD3-related, a prototypal response to DNA damage. UBA1 interacts directly with poly(ADP-ribose) via a solvent-accessible and positively charged patch conserved in the Animalia kingdom but not in Fungi. Thus, ubiquitin activation can anchor to poly(ADP-ribose)-seeded protein assemblies, ensuring the formation of functional ataxia-telangiectasia mutated and RAD3-related-signalling complexes.

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Turner, Thomas, and Thomas Caspari. "When heat casts a spell on the DNA damage checkpoints." Open Biology 4, no. 3 (March 2014): 140008. http://dx.doi.org/10.1098/rsob.140008.

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Peregrine Laziosi (1265–1345), an Italian priest, became the patron saint of cancer patients when the tumour in his left leg miraculously disappeared after he developed a fever. Elevated body temperature can cause tumours to regress and sensitizes cancer cells to agents that break DNA. Why hyperthermia blocks the repair of broken chromosomes by changing the way that the DNA damage checkpoint kinases ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) are activated is an unanswered question. This review discusses the current knowledge of how heat affects the ATR–Chk1 and ATM–Chk2 kinase networks, and provides a possible explanation of why homeothermal organisms such as humans still possess this ancient heat response.

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DeHart, Jason L., Joshua L. Andersen, Erik S. Zimmerman, Orly Ardon, Dong Sung An, Jana Blackett, Baek Kim, and Vicente Planelles. "The Ataxia Telangiectasia-Mutated and Rad3-Related Protein Is Dispensable for Retroviral Integration." Journal of Virology 79, no. 3 (February 1, 2005): 1389–96. http://dx.doi.org/10.1128/jvi.79.3.1389-1396.2005.

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ABSTRACT Integration into the host cell DNA is an essential part of the retroviral life cycle and is required for the productive replication of a retrovirus. Retroviral integration involves cleavage of the host DNA and insertion of the viral DNA, forming an integration intermediate that contains two gaps, each with a viral 5′ flap. The flaps are then removed, and the gap is filled by as yet unidentified nuclease and polymerase activities. It is thought that repair of these gaps flanking the site of retroviral integration is achieved by host DNA repair machinery. The ATM and Rad3-related protein (ATR) is a member of the phosphatidylinositol 3 kinase-related family of protein kinases that play a major role in sensing and triggering repair of DNA lesions in mammalian cells. In an effort to examine the role of ATR in retroviral integration, we used RNA interference to selectively downregulate ATR and measured integration efficiency. In addition, we examined the possible role that Vpr may play in enhancing integration and, in particular, whether activation of ATR by Vpr (Roshal et al., J. Biol. Chem. 278:25879-25886, 2003) will favor human immunodeficiency virus type 1 integration. We conclude that cells in which ATR has been depleted are competent for retroviral integration. We also conclude that the presence of Vpr as a virion-bound protein does not enhance integration of a lentivirus vector in dividing cells.

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Vidal-Eychenié, Sophie, Chantal Décaillet, Jihane Basbous, and Angelos Constantinou. "DNA structure-specific priming of ATR activation by DNA-PKcs." Journal of Cell Biology 202, no. 3 (July 29, 2013): 421–29. http://dx.doi.org/10.1083/jcb.201304139.

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Three phosphatidylinositol-3-kinase–related protein kinases implement cellular responses to DNA damage. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia-telangiectasia mutated respond primarily to DNA double-strand breaks (DSBs). Ataxia-telangiectasia and RAD3-related (ATR) signals the accumulation of replication protein A (RPA)–covered single-stranded DNA (ssDNA), which is caused by replication obstacles. Stalled replication intermediates can further degenerate and yield replication-associated DSBs. In this paper, we show that the juxtaposition of a double-stranded DNA end and a short ssDNA gap triggered robust activation of endogenous ATR and Chk1 in human cell-free extracts. This DNA damage signal depended on DNA-PKcs and ATR, which congregated onto gapped linear duplex DNA. DNA-PKcs primed ATR/Chk1 activation through DNA structure-specific phosphorylation of RPA32 and TopBP1. The synergistic activation of DNA-PKcs and ATR suggests that the two kinases combine to mount a prompt and specific response to replication-born DSBs.

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Asmal, M., E. Dean, J. Evans, M. Middleton, and R. Plummer. "VX-970, selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) protein." Annals of Oncology 26 (March 2015): ii8. http://dx.doi.org/10.1093/annonc/mdv084.4.

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Takeuchi, Makoto, Michihiro Tanikawa, Kazunori Nagasaka, Katsutoshi Oda, Yoshiko Kawata, Shinya Oki, Chuwa Agapiti, et al. "Anti-Tumor Effect of Inhibition of DNA Damage Response Proteins, ATM and ATR, in Endometrial Cancer Cells." Cancers 11, no. 12 (December 1, 2019): 1913. http://dx.doi.org/10.3390/cancers11121913.

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While the incidence of endometrial cancer continues to rise, the therapeutic options remain limited for advanced or recurrent cases, and most cases are resistant to therapy. The anti-tumor effect of many chemotherapeutic drugs and radiotherapy depends on the induction of DNA damage in cancer cells; thus, activation of DNA damage response (DDR) pathways is considered an important factor affecting resistance to therapy. When some DDR pathways are inactivated, inhibition of other DDR pathways can induce cancer-specific synthetic lethality. Therefore, DDR pathways are considered as promising candidates for molecular-targeted therapy for cancer. The crosstalking ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 1 (ATR-Chk1) and ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 2 (ATM-Chk2) pathways are the main pathways of DNA damage response. In this study, we investigated the anti-tumor effect of inhibitors of these pathways in vitro by assessing the effect of the combination of ATM or ATR inhibitors and conventional DNA-damaging therapy (doxorubicin (DXR), cisplatin (CDDP), and irradiation) on endometrial cancer cells. Both the inhibitors enhanced the sensitivity of cells to DXR, CDDP, and irradiation. Moreover, the combination of ATR and Chk1 inhibitors induced DNA damage in endometrial cancer cells and inhibited cell proliferation synergistically. Therefore, these molecular therapies targeting DNA damage response pathways are promising new treatment strategies for endometrial cancer.

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Ward, Irene M., Kay Minn, and Junjie Chen. "UV-induced Ataxia-telangiectasia-mutated and Rad3-related (ATR) Activation Requires Replication Stress." Journal of Biological Chemistry 279, no. 11 (January 23, 2004): 9677–80. http://dx.doi.org/10.1074/jbc.c300554200.

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Tibelius, Alexandra, Joachim Marhold, Hanswalter Zentgraf, Christoph E. Heilig, Heidemarie Neitzel, Bernard Ducommun, Anita Rauch, Anthony D. Ho, Jiri Bartek, and Alwin Krämer. "Microcephalin and pericentrin regulate mitotic entry via centrosome-associated Chk1." Journal of Cell Biology 185, no. 7 (June 22, 2009): 1149–57. http://dx.doi.org/10.1083/jcb.200810159.

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Primary microcephaly, Seckel syndrome, and microcephalic osteodysplastic primordial dwarfism type II (MOPD II) are disorders exhibiting marked microcephaly, with small brain sizes reflecting reduced neuron production during fetal life. Although primary microcephaly can be caused by mutations in microcephalin (MCPH1), cells from patients with Seckel syndrome and MOPD II harbor mutations in ataxia telangiectasia and Rad3 related (ATR) or pericentrin (PCNT), leading to disturbed ATR signaling. In this study, we show that a lack of MCPH1 or PCNT results in a loss of Chk1 from centrosomes with subsequently deregulated activation of centrosomal cyclin B–Cdk1.

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Pancholi, Neha J., Alexander M. Price, and Matthew D. Weitzman. "Take your PIKK: tumour viruses and DNA damage response pathways." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1732 (September 11, 2017): 20160269. http://dx.doi.org/10.1098/rstb.2016.0269.

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Viruses regulate cellular processes to facilitate viral replication. Manipulation of nuclear proteins and pathways by nuclear replicating viruses often causes cellular genome instability that contributes to transformation. The cellular DNA damage response (DDR) safeguards the host to maintain genome integrity, but DNA tumour viruses can manipulate the DDR to promote viral propagation. In this review, we describe the interactions of DNA tumour viruses with the phosphatidylinositol 3-kinase-like protein kinase (PIKK) pathways, which are central regulatory arms of the DDR. We review how signalling through the ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), and DNA-dependent protein kinases (DNA-PK) influences viral life cycles, and how their manipulation by viral proteins may contribute to tumour formation. This article is part of the themed issue ‘Human oncogenic viruses’.

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Pan-Hammarström, Qiang, Aleksi Lähdesmäki, Yaofeng Zhao, Likun Du, Zhihui Zhao, Sicheng Wen, Victor L. Ruiz-Perez, Deborah K. Dunn-Walters, Judith A. Goodship, and Lennart Hammarström. "Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation." Journal of Experimental Medicine 203, no. 1 (January 3, 2006): 99–110. http://dx.doi.org/10.1084/jem.20050595.

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Class switch recombination (CSR) and somatic hypermutation (SHM) are mechanistically related processes initiated by activation-induced cytidine deaminase. Here, we have studied the role of ataxia telangiectasia and Rad3-related protein (ATR) in CSR by analyzing the recombinational junctions, resulting from in vivo switching, in cells from patients with mutations in the ATR gene. The proportion of cells that have switched to immunoglobulin (Ig)A and IgG in the peripheral blood seems to be normal in ATR-deficient (ATRD) patients and the recombined S regions show a normal “blunt end-joining,” but impaired end joining with partially complementary (1–3 bp) DNA ends. There was also an increased usage of microhomology at the μ-α switch junctions, but only up to 9 bp, suggesting that the end-joining pathway requiring longer microhomologies (≥10 bp) may be ATR dependent. The SHM pattern in the Ig variable heavy chain genes is altered, with fewer mutations occurring at A and more mutations at T residues and thus a loss of strand bias in targeting A/T pairs within certain hotspots. These data suggest that the role of ATR is partially overlapping with that of ataxia telangiectasia–mutated protein, but that the former is also endowed with unique functional properties in the repair processes during CSR and SHM.

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Müller, Berndt, Jane Blackburn, Carmen Feijoo, Xiujie Zhao, and Carl Smythe. "DNA-activated protein kinase functions in a newly observed S phase checkpoint that links histone mRNA abundance with DNA replication." Journal of Cell Biology 179, no. 7 (December 24, 2007): 1385–98. http://dx.doi.org/10.1083/jcb.200708106.

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DNA and histone synthesis are coupled and ongoing replication is required to maintain histone gene expression. Here, we expose S phase–arrested cells to the kinase inhibitors caffeine and LY294002. This uncouples DNA replication from histone messenger RNA (mRNA) abundance, altering the efficiency of replication stress–induced histone mRNA down-regulation. Interference with caffeine-sensitive checkpoint kinases ataxia telangiectasia and Rad3 related (ATR)/ataxia telangiectasia mutated (ATM) does not affect histone mRNA down- regulation, which indicates that ATR/ATM alone cannot account for such coupling. LY294002 potentiates caffeine's ability to uncouple histone mRNA stabilization from replication only in cells containing functional DNA-activated protein kinase (DNA-PK), which indicates that DNA-PK is the target of LY294002. DNA-PK is activated during replication stress and DNA-PK signaling is enhanced when ATR/ATM signaling is abrogated. Histone mRNA decay does not require Chk1/Chk2. Replication stress induces phosphorylation of UPF1 but not hairpin-binding protein/stem-loop binding protein at S/TQ sites, which are preferred substrate recognition motifs of phosphatidylinositol 3-kinase–like kinases, which indicates that histone mRNA stability may be directly controlled by ATR/ATM- and DNA-PK–mediated phosphorylation of UPF1.

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Luo, Ying, and Shiyuan Hong. "The Role of Ataxia Telangiectasia Mutant and Rad3-Related DNA Damage Response in Pathogenesis of Human Papillomavirus." Pathogens 9, no. 6 (June 23, 2020): 506. http://dx.doi.org/10.3390/pathogens9060506.

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Human papillomavirus (HPV) infection leads to a variety of benign lesions and malignant tumors such as cervical cancer and head and neck squamous cell carcinoma. Several HPV vaccines have been developed that can help to prevent cervical carcinoma, but these vaccines are only effective in individuals with no prior HPV infection. Thus, it is still important to understand the HPV life cycle and in particular the association of HPV with human pathogenesis. HPV production requires activation of the DNA damage response (DDR), which is a complex signaling network composed of multiple sensors, mediators, transducers, and effectors that safeguard cellular DNAs to maintain the host genome integrity. In this review, we focus on the roles of the ataxia telangiectasia mutant and Rad3-related (ATR) DNA damage response in HPV DNA replication. HPV can induce ATR expression and activate the ATR pathway. Inhibition of the ATR pathway results in suppression of HPV genome maintenance and amplification. The mechanisms underlying this could be through various molecular pathways such as checkpoint signaling and transcriptional regulation. In light of these findings, other downstream mechanisms of the ATR pathway need to be further investigated for better understanding HPV pathogenesis and developing novel ATR DDR-related inhibitors against HPV infection.

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Martínez, Paula, Juana M. Flores, and Maria A. Blasco. "53BP1 deficiency combined with telomere dysfunction activates ATR-dependent DNA damage response." Journal of Cell Biology 197, no. 2 (April 16, 2012): 283–300. http://dx.doi.org/10.1083/jcb.201110124.

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TRF1 protects mammalian telomeres from fusion and fragility. Depletion of TRF1 leads to telomere fusions as well as accumulation of γ-H2AX foci and activation of both the ataxia telangiectasia mutated (ATM)– and the ataxia telangiectasia and Rad3 related (ATR)–mediated deoxyribonucleic acid (DNA) damage response (DDR) pathways. 53BP1, which is also present at dysfunctional telomeres, is a target of ATM that accumulates at DNA double-strand breaks and favors nonhomologous end-joining (NHEJ) repair over ATM-dependent resection and homology-directed repair (homologous recombination [HR]). To address the role of 53BP1 at dysfunctional telomeres, we generated mice lacking TRF1 and 53BP1. 53BP1 deficiency significantly rescued telomere fusions in mouse embryonic fibroblasts (MEFs) lacking TRF1, but they showed evidence of a switch from the NHEJ- to HR-mediated repair of uncapped telomeres. Concomitantly, double-mutant MEFs showed evidence of hyperactivation of the ATR-dependent DDR. In intact mice, combined 53BP1/TRF1 deficiency in stratified epithelia resulted in earlier onset of DNA damage and increased CHK1 phosphorylation during embryonic development, leading to aggravation of skin phenotypes.

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Diernfellner, Axel C. R., Linda Lauinger, Anton Shostak, and Michael Brunner. "A pathway linking translation stress to checkpoint kinase 2 signaling in Neurospora crassa." Proceedings of the National Academy of Sciences 116, no. 35 (August 14, 2019): 17271–79. http://dx.doi.org/10.1073/pnas.1815396116.

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Checkpoint kinase 2 (CHK-2) is a key component of the DNA damage response (DDR). CHK-2 is activated by the PIP3-kinase-like kinases (PI3KKs) ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related protein (ATR), and in metazoan also by DNA-dependent protein kinase catalytic subunit (DNA-PKcs). These DNA damage-dependent activation pathways are conserved and additional activation pathways of CHK-2 are not known. Here we show that PERIOD-4 (PRD-4), the CHK-2 ortholog of Neurospora crassa, is part of a signaling pathway that is activated when protein translation is compromised. Translation stress induces phosphorylation of PRD-4 by a PI3KK distinct from ATM and ATR. Our data indicate that the activating PI3KK is mechanistic target of rapamycin (mTOR). We provide evidence that translation stress is sensed by unbalancing the expression levels of an unstable protein phosphatase that antagonizes phosphorylation of PRD-4 by mTOR complex 1 (TORC1). Hence, Neurospora mTOR and PRD-4 appear to coordinate metabolic state and cell cycle progression.

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Li, Siyu, Tao Wang, Xichang Fei, and Mingjun Zhang. "ATR Inhibitors in Platinum-Resistant Ovarian Cancer." Cancers 14, no. 23 (November 29, 2022): 5902. http://dx.doi.org/10.3390/cancers14235902.

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Platinum-resistant ovarian cancer (PROC) is one of the deadliest types of epithelial ovarian cancer, and it is associated with a poor prognosis as the median overall survival (OS) is less than 12 months. Targeted therapy is a popular emerging treatment method. Several targeted therapies, including those using bevacizumab and poly (ADP-ribose) polymerase inhibitor (PARPi), have been used to treat PROC. Ataxia telangiectasia and RAD3-Related Protein Kinase inhibitors (ATRi) have attracted attention as a promising class of targeted drugs that can regulate the cell cycle and influence homologous recombination (HR) repair. In recent years, many preclinical and clinical studies have demonstrated the efficacy of ATRis in PROC. This review focuses on the anticancer mechanism of ATRis and the progress of research on ATRis for PROC.

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Ramachandran, Sreekanth A., Pradeep S. Jadhavar, Manvendra P. Singh, Ankesh Sharma, Gaurav N. Bagle, Kevin P. Quinn, Po-yin Wong, et al. "Discovery of pyrazolopyrimidine derivatives as novel inhibitors of ataxia telangiectasia and rad3 related protein (ATR)." Bioorganic & Medicinal Chemistry Letters 27, no. 4 (February 2017): 750–54. http://dx.doi.org/10.1016/j.bmcl.2017.01.045.

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Roitinger, Elisabeth, Manuel Hofer, Thomas Köcher, Peter Pichler, Maria Novatchkova, Jianhua Yang, Peter Schlögelhofer, and Karl Mechtler. "Quantitative Phosphoproteomics of the Ataxia Telangiectasia-Mutated (ATM) and Ataxia Telangiectasia-Mutated and Rad3-related (ATR) Dependent DNA Damage Response inArabidopsis thaliana." Molecular & Cellular Proteomics 14, no. 3 (January 5, 2015): 556–71. http://dx.doi.org/10.1074/mcp.m114.040352.

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Savva, Constantinos, Karen De Souza, Reem Ali, Emad A. Rakha, Andrew R. Green, and Srinivasan Madhusudan. "Clinicopathological significance of ataxia telangiectasia-mutated (ATM) kinase and ataxia telangiectasia-mutated and Rad3-related (ATR) kinase in MYC overexpressed breast cancers." Breast Cancer Research and Treatment 175, no. 1 (February 12, 2019): 105–15. http://dx.doi.org/10.1007/s10549-018-05113-8.

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Isono, Makoto, Kazuki Okubo, Takako Asano, and Akinori Sato. "Ataxia telangiectasia and Rad3-related inhibition by AZD6738 enhances gemcitabine-induced cytotoxic effects in bladder cancer cells." PLOS ONE 17, no. 4 (April 12, 2022): e0266476. http://dx.doi.org/10.1371/journal.pone.0266476.

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The ataxia telangiectasia and rad3-related-checkpoint kinase 1 (ATR-CHK1) pathway is involved in DNA damage responses in many cancer cells. ATR inhibitors have been used in clinical trials in combination with radiation or chemotherapeutics; however, their effects against bladder cancer remain unclear. Here, the efficacy of combining gemcitabine with the novel ATR inhibitor AZD6738 was investigated in vitro in three bladder cancer cell lines (J82, T24, and UM-UC-3 cells). The effects of gemcitabine and AZD6738 on cell viability, clonogenicity, cell cycle, and apoptosis were examined. The combined use of gemcitabine and AZD6738 inhibited the viability and colony formation of bladder cancer cells compared to either treatment alone. Gemcitabine (5 nM) and AZD6738 (1 μM) inhibited cell cycle progression, causing cell accumulation in the S phase. Moreover, combined treatment enhanced cleaved poly[ADP-ribose]-polymerase expression alongside the number of annexin V-positive cells, indicating apoptosis induction. Mechanistic investigations showed that AZD6738 treatment inhibited the repair of gemcitabine-induced double-strand breaks by interfering with CHK1. Combining AZD6738 with gemcitabine could therefore be useful for bladder cancer therapy.

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Montales, Katrina, Kenna Ruis, Howard Lindsay, and W. Matthew Michael. "MRN-dependent and independent pathways for recruitment of TOPBP1 to DNA double-strand breaks." PLOS ONE 17, no. 8 (August 2, 2022): e0271905. http://dx.doi.org/10.1371/journal.pone.0271905.

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Ataxia Telangiectasia mutated and RAD3-related (ATR) kinase is activated by DNA replication stress and also by various forms of DNA damage, including DNA double-strand breaks (DSBs). Recruitment to sites of damage is insufficient for ATR activation as one of two known ATR activators, either topoisomerase II-binding protein (TOPBP1) or Ewing’s tumor-associated antigen 1, must also be present for signaling to initiate. Here, we employ our recently established DSB-mediated ATR activation in Xenopus egg extract (DMAX) system to examine how TOPBP1 is recruited to DSBs, so that it may activate ATR. We report that TOPBP1 is only transiently present at DSBs, with a half-life of less than 10 minutes. We also examined the relationship between TOPBP1 and the MRE11-RAD50-NBS1 (MRN), CtBP interacting protein (CtIP), and Ataxia Telangiectasia mutated (ATM) network of proteins. Loss of MRN prevents CtIP recruitment to DSBs, and partially inhibits TOPBP1 recruitment. Loss of CtIP has no impact on either MRN or TOPBP1 recruitment. Loss of ATM kinase activity prevents CtIP recruitment and enhances MRN and TOPBP1 recruitment. These findings demonstrate that there are MRN-dependent and independent pathways that recruit TOPBP1 to DSBs for ATR activation. Lastly, we find that both the 9-1-1 complex and MDC1 are dispensable for TOPBP1 recruitment to DSBs.

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Kabeche, Lilian, Hai Dang Nguyen, Rémi Buisson, and Lee Zou. "A mitosis-specific and R loop–driven ATR pathway promotes faithful chromosome segregation." Science 359, no. 6371 (November 23, 2017): 108–14. http://dx.doi.org/10.1126/science.aan6490.

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The ataxia telangiectasia mutated and Rad3-related (ATR) kinase is crucial for DNA damage and replication stress responses. Here, we describe an unexpected role of ATR in mitosis. Acute inhibition or degradation of ATR in mitosis induces whole-chromosome missegregation. The effect of ATR ablation is not due to altered cyclin-dependent kinase 1 (CDK1) activity, DNA damage responses, or unscheduled DNA synthesis but to loss of an ATR function at centromeres. In mitosis, ATR localizes to centromeres through Aurora A–regulated association with centromere protein F (CENP-F), allowing ATR to engage replication protein A (RPA)–coated centromeric R loops. As ATR is activated at centromeres, it stimulates Aurora B through Chk1, preventing formation of lagging chromosomes. Thus, a mitosis-specific and R loop–driven ATR pathway acts at centromeres to promote faithful chromosome segregation, revealing functions of R loops and ATR in suppressing chromosome instability.

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Kang, Tae-Hong. "Circadian Rhythm of NER and ATR Pathways." Biomolecules 11, no. 5 (May 11, 2021): 715. http://dx.doi.org/10.3390/biom11050715.

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Genomic integrity is constantly insulted by solar ultraviolet (UV) radiation. Adaptative cellular mechanisms called DNA damage responses comprising DNA repair, cell cycle checkpoint, and apoptosis, are believed to be evolved to limit genomic instability according to the photoperiod during a day. As seen in many other key cellular metabolisms, genome surveillance mechanisms against genotoxic UV radiation are under the control of circadian clock systems, thereby exhibiting daily oscillations in their catalytic activities. Indeed, it has been demonstrated that nucleotide excision repair (NER), the sole DNA repair mechanism correcting UV-induced DNA photolesions, and ataxia–telangiectasia-mutated and Rad3-related (ATR)-mediated cell cycle checkpoint kinase are subjected to the robust control of the circadian clock. The molecular foundation for the circadian rhythm of UV-induced DNA damage responses in mammalian cells will be discussed.

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Gusho, Elona, and Laimonis Laimins. "Human Papillomaviruses Target the DNA Damage Repair and Innate Immune Response Pathways to Allow for Persistent Infection." Viruses 13, no. 7 (July 17, 2021): 1390. http://dx.doi.org/10.3390/v13071390.

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Persistent infection with high-risk human papillomaviruses (HPVs) is the major risk factor associated with development of anogenital and oropharyngeal cancers. Initial infection by HPVs occurs into basal epithelial cells where viral genomes are established as nuclear episomes and persist until cleared by the immune response. Productive replication or amplification occurs upon differentiation and is dependent upon activation of the ataxia-telangiectasia mutated (ATM), ataxia telangiectasia and RAD3-related (ATR) DNA damage repair (DDR) pathways. In addition to activating DDR pathways, HPVs must escape innate immune surveillance mechanisms by antagonizing sensors, adaptors, interferons and antiviral gene expression. Both DDR and innate immune pathways are key host mechanisms that crosstalk with each other to maintain homeostasis of cells persistently infected with HPVs. Interestingly, it is still not fully understood why some HPV infections get cleared while others do not. Targeting of these two processes with antiviral therapies may provide opportunities for treatment of cancers caused by high-risk HPVs.

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Wang, Li-Wei, Songwei Jiang, Ying-Hui Yuan, Jilong Duan, Nian-Dong Mao, Zi Hui, Renren Bai, Tian Xie, and Xiang-Yang Ye. "Recent Advances in Synergistic Antitumor Effects Exploited from the Inhibition of Ataxia Telangiectasia and RAD3-Related Protein Kinase (ATR)." Molecules 27, no. 8 (April 12, 2022): 2491. http://dx.doi.org/10.3390/molecules27082491.

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As one of the key phosphatidylinositol 3-kinase-related kinases (PIKKs) family members, ataxia telangiectasia and RAD3-related protein kinase (ATR) is crucial in maintaining mammalian cell genomic integrity in DNA damage response (DDR) and repair pathways. Dysregulation of ATR has been found across different cancer types. In recent years, the inhibition of ATR has been proven to be effective in cancer therapy in preclinical and clinical studies. Importantly, tumor-specific alterations such as ATM loss and Cyclin E1 (CCNE1) amplification are more sensitive to ATR inhibition and are being exploited in synthetic lethality (SL) strategy. Besides SL, synergistic anticancer effects involving ATRi have been reported in an increasing number in recent years. This review focuses on the recent advances in different forms of synergistic antitumor effects, summarizes the pharmacological benefits and ongoing clinical trials behind the biological mechanism, and provides perspectives for future challenges and opportunities. The hope is to draw awareness to the community that targeting ATR should have great potential in developing effective anticancer medicines.

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Kim, Jung-Ae, Michael Kruhlak, Farokh Dotiwala, André Nussenzweig, and James E. Haber. "Heterochromatin is refractory to γ-H2AX modification in yeast and mammals." Journal of Cell Biology 178, no. 2 (July 16, 2007): 209–18. http://dx.doi.org/10.1083/jcb.200612031.

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Double-strand break (DSB) damage in yeast and mammalian cells induces the rapid ATM (ataxia telangiectasia mutated)/ATR (ataxia telangiectasia and Rad3 related)-dependent phosphorylation of histone H2AX (γ-H2AX). In budding yeast, a single endonuclease-induced DSB triggers γ-H2AX modification of 50 kb on either side of the DSB. The extent of γ-H2AX spreading does not depend on the chromosomal sequences. DNA resection after DSB formation causes the slow, progressive loss of γ-H2AX from single-stranded DNA and, after several hours, the Mec1 (ATR)-dependent spreading of γ-H2AX to more distant regions. Heterochromatic sequences are only weakly modified upon insertion of a 3-kb silent HMR locus into a γ-H2AX–covered region. The presence of heterochromatin does not stop the phosphorylation of chromatin more distant from the DSB. In mouse embryo fibroblasts, γ-H2AX distribution shows that γ-H2AX foci increase in size as chromatin becomes more accessible. In yeast, we see a high level of constitutive γ-H2AX in telomere regions in the absence of any exogenous DNA damage, suggesting that yeast chromosome ends are transiently detected as DSBs.

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Ma, Shuai, Cheng Cao, Shiyou Che, Yuejiao Wang, Dongxue Su, Shuai Liu, Wenchen Gong, et al. "PHF8-promoted TOPBP1 demethylation drives ATR activation and preserves genome stability." Science Advances 7, no. 19 (May 2021): eabf7684. http://dx.doi.org/10.1126/sciadv.abf7684.

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The checkpoint kinase ATR [ATM (ataxia-telangiectasia mutated) and rad3-related] is a master regulator of DNA damage response. Yet, how ATR activity is regulated remains to be investigated. We report here that histone demethylase PHF8 (plant homeodomain finger protein 8) plays a key role in ATR activation and replication stress response. Mechanistically, PHF8 interacts with and demethylates TOPBP1 (DNA topoisomerase 2-binding protein 1), an essential allosteric activator of ATR, under unperturbed conditions, but replication stress results in PHF8 phosphorylation and dissociation from TOPBP1. Consequently, hypomethylated TOPBP1 facilitates RAD9 (RADiation sensitive 9) binding and chromatin loading of the TOPBP1-RAD9 complex to fully activate ATR and thus safeguard the genome and protect cells against replication stress. Our study uncovers a demethylation and phosphorylation code that controls the assembly of TOPBP1-scaffolded protein complex, and provides molecular insight into non-histone methylation switch in ATR activation.

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Ngoi, Natalie Y. L., Guang Peng, and Timothy A. Yap. "A Tale of Two Checkpoints: ATR Inhibition and PD-(L)1 Blockade." Annual Review of Medicine 73, no. 1 (January 27, 2022): 231–50. http://dx.doi.org/10.1146/annurev-med-042320-025136.

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Innate immunity and the DNA damage response (DDR) pathway are inextricably linked. Within the DDR, ataxia telangiectasia and Rad3-related (ATR) is a key kinase responsible for sensing replication stress and facilitating DNA repair through checkpoint activation, cell cycle arrest, and promotion of fork recovery. Recent studies have shed light on the immunomodulatory role of the ATR-CHK1 pathway in the tumor microenvironment and the specific effects of ATR inhibition in stimulating an innate immune response. With several potent and selective ATR inhibitors in developmental pipelines, the combination of dual ATR and PD-(L)1 blockade has attracted increasing interest in cancer therapy. In this review, we summarize the clinical and preclinical data supporting the combined inhibition of ATR and PD-(L)1, discuss the potential challenges surrounding this approach, and highlight biomarkers relevant for selected patients who are most likely to benefit from the blockade of these two checkpoints.

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Bothou, Christina, Ashish Sharma, Adrian Oo, Baek Kim, Pal Perge, Peter Igaz, Cristina L. Ronchi, Igor Shapiro, and Constanze Hantel. "Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment." Cancers 13, no. 16 (August 20, 2021): 4200. http://dx.doi.org/10.3390/cancers13164200.

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Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.

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Lu, Huiming, Janapriya Saha, Pauline J. Beckmann, Eric A. Hendrickson, and Anthony J. Davis. "DNA-PKcs promotes chromatin decondensation to facilitate initiation of the DNA damage response." Nucleic Acids Research 47, no. 18 (August 9, 2019): 9467–79. http://dx.doi.org/10.1093/nar/gkz694.

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Abstract The DNA damage response (DDR) encompasses the cellular response to DNA double-stranded breaks (DSBs), and includes recognition of the DSB, recruitment of numerous factors to the DNA damage site, initiation of signaling cascades, chromatin remodeling, cell-cycle checkpoint activation, and repair of the DSB. Key drivers of the DDR are multiple members of the phosphatidylinositol 3-kinase-related kinase family, including ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). ATM and ATR modulate multiple portions of the DDR, but DNA-PKcs is believed to primarily function in the DSB repair pathway, non-homologous end joining. Utilizing a human cell line in which the kinase domain of DNA-PKcs is inactivated, we show here that DNA-PKcs kinase activity is required for the cellular response to DSBs immediately after their induction. Specifically, DNA-PKcs kinase activity initiates phosphorylation of the chromatin factors H2AX and KAP1 following ionizing radiation exposure and drives local chromatin decondensation near the DSB site. Furthermore, loss of DNA-PKcs kinase activity results in a marked decrease in the recruitment of numerous members of the DDR machinery to DSBs. Collectively, these results provide clear evidence that DNA-PKcs activity is pivotal for the initiation of the DDR.

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Göhler, Thomas, Simone Sabbioneda, Catherine M. Green, and Alan R. Lehmann. "ATR-mediated phosphorylation of DNA polymerase η is needed for efficient recovery from UV damage." Journal of Cell Biology 192, no. 2 (January 17, 2011): 219–27. http://dx.doi.org/10.1083/jcb.201008076.

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DNA polymerase η (polη) belongs to the Y-family of DNA polymerases and facilitates translesion synthesis past UV damage. We show that, after UV irradiation, polη becomes phosphorylated at Ser601 by the ataxia-telangiectasia mutated and Rad3-related (ATR) kinase. DNA damage–induced phosphorylation of polη depends on its physical interaction with Rad18 but is independent of PCNA monoubiquitination. It requires the ubiquitin-binding domain of polη but not its PCNA-interacting motif. ATR-dependent phosphorylation of polη is necessary to restore normal survival and postreplication repair after ultraviolet irradiation in xeroderma pigmentosum variant fibroblasts, and is involved in the checkpoint response to UV damage. Taken together, our results provide evidence for a link between DNA damage–induced checkpoint activation and translesion synthesis in mammalian cells.

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Li, Pengcheng, Chenchen Xu, Xiaoyan Zhang, Cheng Cao, Xuejuan Wang, and Gang Cai. "Single-stranded RNA viruses activate and hijack host apical DNA damage response kinases for efficient viral replication." Genome Instability & Disease 3, no. 2 (February 28, 2022): 83–87. http://dx.doi.org/10.1007/s42764-022-00064-3.

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AbstractThe ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) are apical kinases that orchestrate the multifaceted DNA damage response (DDR) to a variety of genotoxic insults and regulate genomic stability. Whether RNA virus also manipulates the host’s DDR machine to facilitate replication is largely unknown. In this study, we revealed that single-stranded RNA virus replication specifically elicits host ATM- and ATR-mediated pathway activation and boosts their expression. The activated ATM and ATR are hijacked to the virus replication factory in the cytoplasm and facilitate viral gene expression and replication. Specific inhibitors targeting ATM and ATR strikingly block the viral proliferation and replication and inhibit expression of virus proteins. Our results reveal a novel, or otherwise noncanonical, conserved function of ATM/ATR outside DDR in promoting the replication of single-stranded RNA virus and provide an important mechanism of host–pathogen interactions.

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Xiao, Gu, Pao Kue, Rahul Bhosle, and Jill Bargonetti. "Decarbamoyl mitomycin C (DMC) activates p53-independent ataxia telangiectasia and rad3 related protein (ATR) chromatin eviction." Cell Cycle 14, no. 5 (March 4, 2015): 744–54. http://dx.doi.org/10.1080/15384101.2014.997517.

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Nam, Edward A., Runxiang Zhao, Gloria G. Glick, Carol E. Bansbach, David B. Friedman, and David Cortez. "Thr-1989 Phosphorylation Is a Marker of Active Ataxia Telangiectasia-mutated and Rad3-related (ATR) Kinase." Journal of Biological Chemistry 286, no. 33 (June 24, 2011): 28707–14. http://dx.doi.org/10.1074/jbc.m111.248914.

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Abdel-Hafiz, Ahmed, Krishna Madhavan, Ilango Balakrishnan, Angela Pierce, Dong Wang, Etienne Danis, Natalie Serkova, Sujatha Venkataraman, and Rajeev Vibhakar. "MBRS-71. ATAXIA TELANGIECTASIA AND RAD3-RELATED PROTEIN ATTENUATES DNA DAMAGE AND IS A THERAPEUTIC TARGET IN Myc-DRIVEN MEDULLOBLASTOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii411. http://dx.doi.org/10.1093/neuonc/noaa222.575.

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Abstract Group 3 medulloblastoma tumors (Myc-MB), and particularly the 3γ subtype, have the worst prognosis and show a 5-year overall survival of less than 40%. Group 3 tumors are often accompanied by Myc amplification and have a higher rate of metastatic disease and relapse. Unfortunately, therapeutic strategies to target Mychave remained elusive. Further, the relapse of the MB has been linked to DNA replication stress. Ataxia telangiectasia and Rad3-related protein (ATR) senses persistent DNA damage, which arises due to replication stress, and activates damage checkpoints, thereby leading to increased cell survival. ATR is highly expressed in MB and is thought to contribute to undisturbed DNA replication to protect genomic integrity. Yet, the exact underlying mechanisms involving ATR are still unclear in MB. Inhibition of ATR (ATRi) using the ATR inhibitor, AZD6738, suppressed clonogenicity and cell self-renewal in Myc-MB. ATRi in Myc-MB cell lines downregulated Chk1 and upregulated P21. ATRi also induced cell cycle arrest and increased apoptosis in Myc-MB cell lines. Further, mice with orthotopic xenografts treated with ATR inhibitor survived significantly longer than control mice. High-throughput drug screening showed ATRi to be synergistic with chemotherapeutic agents including gemcitabine, cisplatin and topotecan. The treatment of Myc-MB cells with ATR inhibitor in combination with gemcitabine and with radiation increased in expression of DNA damage markers. These findings emphasize the role of ATR in alleviating DNA replication stress and that its inhibition is critical to the treatment of Myc-MB.

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Jette, Nicholas R., Mehul Kumar, Suraj Radhamani, Greydon Arthur, Siddhartha Goutam, Steven Yip, Michael Kolinsky, Gareth J. Williams, Pinaki Bose, and Susan P. Lees-Miller. "ATM-Deficient Cancers Provide New Opportunities for Precision Oncology." Cancers 12, no. 3 (March 14, 2020): 687. http://dx.doi.org/10.3390/cancers12030687.

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Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death.

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Southgate, Harriet E. D., Lindi Chen, Deborah A. Tweddle, and Nicola J. Curtin. "ATR Inhibition Potentiates PARP Inhibitor Cytotoxicity in High Risk Neuroblastoma Cell Lines by Multiple Mechanisms." Cancers 12, no. 5 (April 28, 2020): 1095. http://dx.doi.org/10.3390/cancers12051095.

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Background: High risk neuroblastoma (HR-NB) is one the most difficult childhood cancers to cure. These tumours frequently present with DNA damage response (DDR) defects including loss or mutation of key DDR genes, oncogene-induced replication stress (RS) and cell cycle checkpoint dysfunction. Aim: To identify biomarkers of sensitivity to inhibition of Ataxia telangiectasia and Rad3 related (ATR), a DNA damage sensor, and poly (ADP-ribose) polymerase (PARP), which is required for single strand break repair. We also hypothesise that combining ATR and PARP inhibition is synergistic. Methods: Single agent sensitivity to VE-821 (ATR inhibitor) and olaparib (PARP inhibitor), and the combination, was determined using cell proliferation and clonogenic assays, in HR-NB cell lines. Basal expression of DDR proteins, including ataxia telangiectasia mutated (ATM) and ATR, was assessed using Western blotting. CHK1S345 and H2AXS129 phosphorylation was assessed using Western blotting to determine ATR activity and RS, respectively. RS and homologous recombination repair (HRR) activity was also measured by γH2AX and Rad51 foci formation using immunofluorescence. Results: MYCN amplification and/or low ATM protein expression were associated with sensitivity to VE-821 (p < 0.05). VE-821 was synergistic with olaparib (CI value 0.04–0.89) independent of MYCN or ATM status. Olaparib increased H2AXS129 phosphorylation which was further increased by VE-821. Olaparib-induced Rad51 foci formation was reduced by VE-821 suggesting inhibition of HRR. Conclusion: RS associated with MYCN amplification, ATR loss or PARP inhibition increases sensitivity to the ATR inhibitor VE-821. These findings suggest a potential therapeutic strategy for the treatment of HR-NB.

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de Lange, Titia. "Shelterin-Mediated Telomere Protection." Annual Review of Genetics 52, no. 1 (November 23, 2018): 223–47. http://dx.doi.org/10.1146/annurev-genet-032918-021921.

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For more than a decade, it has been known that mammalian cells use shelterin to protect chromosome ends. Much progress has been made on the mechanism by which shelterin prevents telomeres from inadvertently activating DNA damage signaling and double-strand break (DSB) repair pathways. Shelterin averts activation of three DNA damage response enzymes [the ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases and poly(ADP-ribose) polymerase 1 (PARP1)], blocks three DSB repair pathways [classical nonhomologous end joining (c-NHEJ), alternative (alt)-NHEJ, and homology-directed repair (HDR)], and prevents hyper-resection at telomeres. For several of these functions, mechanistic insights have emerged. In addition, much has been learned about how shelterin maintains the telomeric 3′ overhang, forms and protects the t-loop structure, and promotes replication through telomeres. These studies revealed that shelterin is compartmentalized, with individual subunits dedicated to distinct aspects of the end-protection problem. This review focuses on the current knowledge of shelterin-mediated telomere protection, highlights differences between human and mouse shelterin, and discusses some of the questions that remain.

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Kulkarni, Amit, and Kumuda C. Das. "Differential roles of ATR and ATM in p53, Chk1, and histone H2AX phosphorylation in response to hyperoxia: ATR-dependent ATM activation." American Journal of Physiology-Lung Cellular and Molecular Physiology 294, no. 5 (May 2008): L998—L1006. http://dx.doi.org/10.1152/ajplung.00004.2008.

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Elevated level of oxygen (hyperoxia) is widely used in critical care units and in respiratory insufficiencies. In addition, hyperoxia has been implicated in many diseases such as bronchopulmonary dysplasia or acute respiratory distress syndrome. Although hyperoxia is known to cause DNA base modifications and strand breaks, the DNA damage response has not been adequately investigated. We have investigated the effect of hyperoxia on DNA damage signaling and show that hyperoxia is a unique stress that activates the ataxia telangiectasia mutant (ATM)- and Rad3-related protein kinase (ATR)-dependent p53 phosphorylations (Ser6, -15, -37, and -392), phosphorylation of histone H2AX (Ser139), and phosphorylation of checkpoint kinase 1 (Chk1). In addition, we show that phosphorylation of p53 (Ser6) and histone H2AX (Ser139) depend on both ATM and ATR. We demonstrate that ATR activation precedes ATM activation in hyperoxia. Finally, we show that ATR is required for ATM activation in hyperoxia. Taken together, we report that ATR is the major DNA damage signal transducer in hyperoxia that activates ATM.

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Saldivar, Joshua C., Stephan Hamperl, Michael J. Bocek, Mingyu Chung, Thomas E. Bass, Fernanda Cisneros-Soberanis, Kumiko Samejima, et al. "An intrinsic S/G2 checkpoint enforced by ATR." Science 361, no. 6404 (August 23, 2018): 806–10. http://dx.doi.org/10.1126/science.aap9346.

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The cell cycle is strictly ordered to ensure faithful genome duplication and chromosome segregation. Control mechanisms establish this order by dictating when a cell transitions from one phase to the next. Much is known about the control of the G1/S, G2/M, and metaphase/anaphase transitions, but thus far, no control mechanism has been identified for the S/G2 transition. Here we show that cells transactivate the mitotic gene network as they exit the S phase through a CDK1 (cyclin-dependent kinase 1)–directed FOXM1 phosphorylation switch. During normal DNA replication, the checkpoint kinase ATR (ataxia-telangiectasia and Rad3-related) is activated by ETAA1 to block this switch until the S phase ends. ATR inhibition prematurely activates FOXM1, deregulating the S/G2 transition and leading to early mitosis, underreplicated DNA, and DNA damage. Thus, ATR couples DNA replication with mitosis and preserves genome integrity by enforcing an S/G2 checkpoint.

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Rozpędek, Wioletta, Dariusz Pytel, Alicja Nowak-Zduńczyk, Dawid Lewko, Radosław Wojtczak, J. Alan Diehl, and Ireneusz Majsterek. "Breaking the DNA Damage Response via Serine/Threonine Kinase Inhibitors to Improve Cancer Treatment." Current Medicinal Chemistry 26, no. 8 (May 16, 2019): 1425–45. http://dx.doi.org/10.2174/0929867325666180117102233.

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Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/ threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptotic cell death. Interestingly, key components of DDR signaling networks may constitute an attractive target for anti-cancer therapy through two distinct potential approaches: as chemoand radiosensitizers to enhance the effectiveness of currently used genotoxic treatment or as single agents to exploit defects in DDR in cancer cells via synthetic lethal approach. Moreover, the newest data reported that serine/threonine protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is also closely associated with cancer development and progression. Thereby, utilization of small-molecule, serine/threonine kinase inhibitors may provide a novel, groundbreaking, anti-cancer treatment strategy. Currently, a range of potent, highlyselective toward ATM, ATR and PERK inhibitors has been discovered, but after foregoing study, additional investigations are necessary for their future clinical use.

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Wong, Wen-Kyle, Francisco D. C. Guerra Liberal, and Stephen J. McMahon. "DNA Repair Inhibitors Potentiate Fractionated Radiotherapy More Than Single-Dose Radiotherapy in Breast Cancer Cells." Cancers 14, no. 15 (August 4, 2022): 3794. http://dx.doi.org/10.3390/cancers14153794.

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Pharmacological inhibitors of DNA damage response (DDR) proteins, such as the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) kinases and poly (ADP-ribose) polymerase (PARP), have been developed to overcome tumor radioresistance. Despite demonstrating radiosensitization preclinically, they have performed suboptimally in clinical trials, possibly due to an incomplete understanding of the influence of DDR inhibition on ionizing radiation (IR) dose fractionation and sublethal damage repair. Hence, this study aimed to evaluate the radiosensitizing ability under fractionation of ATM inhibitor AZD0156, ATR inhibitor AZD6738 and PARP inhibitor AZD2281 (olaparib), utilizing MDA-MB-231 and MCF-7 human breast cancer cells. Clonogenic assays were performed to assess cell survival and sublethal damage repair after treatment with DDR inhibitors and either single-dose or fractionated IR. Immunofluorescence microscopy was utilized to evaluate DNA double-strand break repair kinetics. Cell cycle distributions were investigated using flow cytometry. All inhibitors showed significant radiosensitization, which was significantly greater following fractionated IR than single-dose IR. They also led to more unrepaired DNA double-strand breaks at 24 h post-IR. This study provides preclinical evidence for the role of AZD0156, AZD6738 and olaparib as radiosensitizing agents. Still, it highlights the need to evaluate these drugs in fractionated settings mirroring clinical practice to optimize the trial design.

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Lee, Alan Yueh-Luen, Takuya Chiba, Lan N. Truong, An Ning Cheng, Johnny Do, Michael Jeffrey Cho, Longchuan Chen, and Xiaohua Wu. "Dbf4 Is Direct Downstream Target of Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia and Rad3-related (ATR) Protein to Regulate Intra-S-phase Checkpoint." Journal of Biological Chemistry 287, no. 4 (November 28, 2011): 2531–43. http://dx.doi.org/10.1074/jbc.m111.291104.

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Dok, Rüveyda, Mary Glorieux, Marieke Bamps, and Sandra Nuyts. "Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers." International Journal of Molecular Sciences 22, no. 4 (February 3, 2021): 1504. http://dx.doi.org/10.3390/ijms22041504.

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Radiotherapy (RT) has a central role in head and neck squamous cell carcinoma (HNSCC) treatment. Targeted therapies modulating DNA damage response (DDR) and more specific cell cycle checkpoints can improve the radiotherapeutic response. Here, we assessed the influence of ataxia-telangiectasia mutated and Rad3-related (ATR) inhibition with the ATR inhibitor AZD6738 on RT response in both human papillomavirus (HPV)-negative and HPV-positive HNSCC. We found that ATR inhibition enhanced RT response in HPV-negative and HPV-positive cell lines independent of HPV status. The radiosensitizing effect of AZD6738 was correlated with checkpoint kinase 1 (CHK1)-mediated abrogation of G2/M-arrest. This resulted in the inhibition of RT-induced DNA repair and in an increase in the percentage of micronucleated cells. We validated the enhanced RT response in HPV-negative and HPV-positive xenograft models. These data demonstrate the potential use of ATR inhibition in combination with RT as a treatment option for both HPV-negative and HPV-positive HNSCC patients.

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Lindsey-Boltz, Laura A., and Aziz Sancar. "Tethering DNA Damage Checkpoint Mediator Proteins Topoisomerase IIβ-binding Protein 1 (TopBP1) and Claspin to DNA Activates Ataxia-Telangiectasia Mutated and RAD3-related (ATR) Phosphorylation of Checkpoint Kinase 1 (Chk1)." Journal of Biological Chemistry 286, no. 22 (April 18, 2011): 19229–36. http://dx.doi.org/10.1074/jbc.m111.237958.

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The ataxia-telangiectasia mutated and RAD3-related (ATR) kinase initiates DNA damage signaling pathways in human cells after DNA damage such as that induced upon exposure to ultraviolet light by phosphorylating many effector proteins including the checkpoint kinase Chk1. The conventional view of ATR activation involves a universal signal consisting of genomic regions of replication protein A-covered single-stranded DNA. However, there are some indications that the ATR-mediated checkpoint can be activated by other mechanisms. Here, using the well defined Escherichia coli lac repressor/operator system, we have found that directly tethering the ATR activator topoisomerase IIβ-binding protein 1 (TopBP1) to DNA is sufficient to induce ATR phosphorylation of Chk1 in an in vitro system as well as in vivo in mammalian cells. In addition, we find synergistic activation of ATR phosphorylation of Chk1 when the mediator protein Claspin is also tethered to the DNA with TopBP1. Together, these findings indicate that crowding of checkpoint mediator proteins on DNA is sufficient to activate the ATR kinase.

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Nam, Edward A., and David Cortez. "ATR signalling: more than meeting at the fork." Biochemical Journal 436, no. 3 (May 27, 2011): 527–36. http://dx.doi.org/10.1042/bj20102162.

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Preservation of genome integrity via the DNA-damage response is critical to prevent disease. ATR (ataxia telangiectasia mutated- and Rad3-related) is essential for life and functions as a master regulator of the DNA-damage response, especially during DNA replication. ATR controls and co-ordinates DNA replication origin firing, replication fork stability, cell cycle checkpoints and DNA repair. Since its identification 15 years ago, a model of ATR activation and signalling has emerged that involves localization to sites of DNA damage and activation through protein–protein interactions. Recent research has added an increasingly detailed understanding of the canonical ATR pathway, and an appreciation that the canonical model does not fully capture the complexity of ATR regulation. In the present article, we review the ATR signalling process, focusing on mechanistic findings garnered from the identification of new ATR-interacting proteins and substrates. We discuss how to incorporate these new insights into a model of ATR regulation and point out the significant gaps in our understanding of this essential genome-maintenance pathway.

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O'Driscoll, Mark, Victor L. Ruiz-Perez, C. Geoffrey Woods, Penny A. Jeggo, and Judith A. Goodship. "A splicing mutation affecting expression of ataxia–telangiectasia and Rad3–related protein (ATR) results in Seckel syndrome." Nature Genetics 33, no. 4 (March 17, 2003): 497–501. http://dx.doi.org/10.1038/ng1129.

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Biskup, Edyta, David Gram Naym, and Robert Gniadecki. "Small-molecule inhibitors of Ataxia Telangiectasia and Rad3 related kinase (ATR) sensitize lymphoma cells to UVA radiation." Journal of Dermatological Science 84, no. 3 (December 2016): 239–47. http://dx.doi.org/10.1016/j.jdermsci.2016.09.010.

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Al-Subhi, Nouf, Reem Ali, Tarek Abdel-Fatah, Paul M. Moseley, Stephen Y. T. Chan, Andrew R. Green, Ian O. Ellis, Emad A. Rakha, and Srinivasan Madhusudan. "Targeting ataxia telangiectasia-mutated- and Rad3-related kinase (ATR) in PTEN-deficient breast cancers for personalized therapy." Breast Cancer Research and Treatment 169, no. 2 (February 2, 2018): 277–86. http://dx.doi.org/10.1007/s10549-018-4683-4.

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Zhang, Jennifer Q. J., Sayanthooran Saravanabavan, and Gopala K. Rangan. "Effect of Reducing Ataxia-Telangiectasia Mutated (ATM) in Experimental Autosomal Dominant Polycystic Kidney Disease." Cells 10, no. 3 (March 3, 2021): 532. http://dx.doi.org/10.3390/cells10030532.

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The DNA damage response (DDR) pathway is upregulated in autosomal dominant polycystic kidney disease (ADPKD) but its functional role is not known. The ataxia-telangiectasia mutated (ATM) and AT and Rad3-related (ATR) protein kinases are key proximal transducers of the DDR. This study hypothesized that reducing either ATM or ATR attenuates kidney cyst formation and growth in experimental ADPKD. In vitro, pharmacological ATM inhibition by AZD0156 reduced three-dimensional cyst growth in MDCK and human ADPKD cells by up to 4.4- and 4.1-fold, respectively. In contrast, the ATR inhibitor, VE-821, reduced in vitro MDCK cyst growth but caused dysplastic changes. In vivo, treatment with AZD0156 by oral gavage for 10 days reduced renal cell proliferation and increased p53 expression in Pkd1RC/RC mice (a murine genetic ortholog of ADPKD). However, the progression of cystic kidney disease in Pkd1RC/RC mice was not altered by genetic ablation of ATM from birth, in either heterozygous (Pkd1RC/RC/Atm+/−) or homozygous (Pkd1RC/RC/Atm−/−) mutant mice at 3 months. In conclusion, despite short-term effects on reducing renal cell proliferation, chronic progression was not altered by reducing ATM in vivo, suggesting that this DDR kinase is dispensable for kidney cyst formation in ADPKD.

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Journal articles on the topic 'Ataxia Telangiectasia and Rad3-related (ATR)'

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