Journal articles: 'Genotoxic stress response'

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Antoch, Marina P., and Roman V. Kondratov. "Circadian Proteins and Genotoxic Stress Response." Circulation Research 106, no. 1 (January 8, 2010): 68–78. http://dx.doi.org/10.1161/circresaha.109.207076.

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Chen, Ting-Yu, Bu-Miin Huang, Tang K. Tang, Yu-Ying Chao, Xiao-Yi Xiao, Pei-Rong Lee, Li-Yun Yang, and Chia-Yih Wang. "Genotoxic stress-activated DNA-PK-p53 cascade and autophagy cooperatively induce ciliogenesis to maintain the DNA damage response." Cell Death & Differentiation 28, no. 6 (January 18, 2021): 1865–79. http://dx.doi.org/10.1038/s41418-020-00713-8.

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AbstractThe DNA-PK maintains cell survival when DNA damage occurs. In addition, aberrant activation of the DNA-PK induces centrosome amplification, suggesting additional roles for this kinase. Here, we showed that the DNA-PK-p53 cascade induced primary cilia formation (ciliogenesis), thus maintaining the DNA damage response under genotoxic stress. Treatment with genotoxic drugs (etoposide, neocarzinostatin, hydroxyurea, or cisplatin) led to ciliogenesis in human retina (RPE1), trophoblast (HTR8), lung (A459), and mouse Leydig progenitor (TM3) cell lines. Upon genotoxic stress, several DNA damage signaling were activated, but only the DNA-PK-p53 cascade contributed to ciliogenesis, as pharmacological inhibition or genetic depletion of this pathway decreased genotoxic stress-induced ciliogenesis. Interestingly, in addition to localizing to the nucleus, activated DNA-PK localized to the base of the primary cilium (mother centriole) and daughter centriole. Genotoxic stress also induced autophagy. Inhibition of autophagy initiation or lysosomal degradation or depletion of ATG7 decreased genotoxic stress-induced ciliogenesis. Besides, inhibition of ciliogenesis by depletion of IFT88 or CEP164 attenuated the genotoxic stress-induced DNA damage response. Thus, our study uncovered the interplay among genotoxic stress, the primary cilium, and the DNA damage response.

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Dbaibo, G. S., M. Y. Pushkareva, R. A. Rachid, N. Alter, M. J. Smyth, L. M. Obeid, and Y. A. Hannun. "p53-dependent ceramide response to genotoxic stress." Journal of Clinical Investigation 102, no. 2 (July 15, 1998): 329–39. http://dx.doi.org/10.1172/jci1180.

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Shi, Qing-Mei, Yan-Ming Wang, Xin-De Zheng, Raymond Teck Ho Lee, and Yue Wang. "Critical Role of DNA Checkpoints in Mediating Genotoxic-Stress–induced Filamentous Growth inCandida albicans." Molecular Biology of the Cell 18, no. 3 (March 2007): 815–26. http://dx.doi.org/10.1091/mbc.e06-05-0442.

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The polymorphic fungus Candida albicans switches from yeast to filamentous growth in response to a range of genotoxic insults, including inhibition of DNA synthesis by hydroxyurea (HU) or aphidicolin (AC), depletion of the ribonucleotide-reductase subunit Rnr2p, and DNA damage induced by methylmethane sulfonate (MMS) or UV light (UV). Deleting RAD53, which encodes a downstream effector kinase for both the DNA-replication and DNA-damage checkpoint pathways, completely abolished the filamentous growth caused by all the genotoxins tested. Deleting RAD9, which encodes a signal transducer of the DNA-damage checkpoint, specifically blocked the filamentous growth induced by MMS or UV but not that induced by HU or AC. Deleting MRC1, the counterpart of RAD9 in the DNA-replication checkpoint, impaired DNA synthesis and caused cell elongation even in the absence of external genotoxic insults. Together, the results indicate that the DNA-replication/damage checkpoints are critically required for the induction of filamentous growth by genotoxic stress. In addition, either of two mutations in the FHA1 domain of Rad53p, G65A, and N104A, nearly completely blocked the filamentous-growth response but had no significant deleterious effect on cell-cycle arrest. These results suggest that the FHA domain, known for its ability to bind phosphopeptides, has an important role in mediating genotoxic-stress–induced filamentous growth and that such growth is a specific, Rad53p-regulated cellular response in C. albicans.

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Sun, X., H. Shimizu, and K. Yamamoto. "Identification of a novel p53 promoter element involved in genotoxic stress-inducible p53 gene expression." Molecular and Cellular Biology 15, no. 8 (August 1995): 4489–96. http://dx.doi.org/10.1128/mcb.15.8.4489.

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p53 is recruited in response to DNA-damaging genotoxic stress and plays an important role in maintaining the integrity of the genome. We show that exposure of cells to various genotoxic agents, including anticancer drugs such as mitomycin and 5-fluorouracil, results in an increase in p53 mRNA levels and in p53 promoter activation, indicating that the p53 genotoxic stress response is partly regulated at the transcriptional level. The results of the p53 promoter analysis show that a novel p53 promoter element, termed a p53 core promoter element (from -70 to -46), is essential for basal p53 promoter activity and promoter activation induced by genotoxic agents such as anticancer drugs and UV. Although a kappa B motif partially overlaps with this element and those genotoxic agents activate NF-kappa B, it does not play a major role in p53 genotoxic stress response: NF-kappa B p65 expression did not induce significant p53 promoter activation, and NF-kappa B inhibitors (N-acetyl cysteine and I kappa B alpha) did not inhibit genotoxic stress-inducible p53 promoter activation. Finally, we characterized nuclear factors, the binding of which to the p53 core promoter element is essential for basal p53 promoter activity and p53 promoter activation induced by genotoxic agents.

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Liu, Li, Jiri Veis, Wolfgang Reiter, Edwin Motari, Catherine E. Costello, John C. Samuelson, Gustav Ammerer, and David E. Levin. "Regulation of Pkc1 Hyper-Phosphorylation by Genotoxic Stress." Journal of Fungi 7, no. 10 (October 17, 2021): 874. http://dx.doi.org/10.3390/jof7100874.

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The cell wall integrity (CWI) signaling pathway is best known for its roles in cell wall biogenesis. However, it is also thought to participate in the response to genotoxic stress. The stress-activated protein kinase Mpk1 (Slt2, is activated by DNA damaging agents through an intracellular mechanism that does not involve the activation of upstream components of the CWI pathway. Additional observations suggest that protein kinase C (Pkc1), the top kinase in the CWI signaling cascade, also has a role in the response to genotoxic stress that is independent of its recognized function in the activation of Mpk1. Pkc1 undergoes hyper-phosphorylation specifically in response to genotoxic stress; we have found that this requires the DNA damage checkpoint kinases Mec1 (Mitosis Entry Checkpoint) and Tel1 (TELomere maintenance), but not their effector kinases. We demonstrate that the casein kinase 1 (CK1) ortholog, Hrr25 (HO and Radiation Repair), previously implicated in the DNA damage transcriptional response, associates with Pkc1 under conditions of genotoxic stress. We also found that the induced association of Hrr25 with Pkc1 requires Mec1 and Tel1, and that Hrr25 catalytic activity is required for Pkc1-hyperphosphorylation, thereby delineating a pathway from the checkpoint kinases to Pkc1. We used SILAC mass spectrometry to identify three residues within Pkc1 the phosphorylation of which was stimulated by genotoxic stress. We mutated these residues as well as a collection of 13 phosphorylation sites within the regulatory domain of Pkc1 that fit the consensus for CK1 sites. Mutation of the 13 Pkc1 phosphorylation sites blocked hyper-phosphorylation and diminished RNR3 (RiboNucleotide Reductase) basal expression and induction by genotoxic stress, suggesting that Pkc1 plays a role in the DNA damage transcriptional response.

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Suh, Yousin, Kang-Ae Lee, Woo-Ho Kim, Bok-Ghee Han, Jan Vijg, and Sang Chul Park. "Aging alters the apoptotic response to genotoxic stress." Nature Medicine 8, no. 1 (January 2002): 3–4. http://dx.doi.org/10.1038/nm0102-3.

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Dutertre, Martin, Gabriel Sanchez, Marie-Cécile De Cian, Jérôme Barbier, Etienne Dardenne, Lise Gratadou, Gwendal Dujardin, Catherine Le Jossic-Corcos, Laurent Corcos, and Didier Auboeuf. "Cotranscriptional exon skipping in the genotoxic stress response." Nature Structural & Molecular Biology 17, no. 11 (October 24, 2010): 1358–66. http://dx.doi.org/10.1038/nsmb.1912.

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FORNACE, ALBERT J., JOANY JACKMAN, M. CHRISTINE HOLLANDER, BARBARA HOFFMAN-LIEBERMANN, and DAN A. LIEBERMANN. "Genotoxic-Stress-Response Genes and Growth-Arrest Genes." Annals of the New York Academy of Sciences 663, no. 1 Aging and Cel (November 1992): 139–53. http://dx.doi.org/10.1111/j.1749-6632.1992.tb38657.x.

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10

Kumari, Nidhi, M. Abul Hassan, Xiangdong Lu, Robert G. Roeder, and Debabrata Biswas. "AFF1 acetylation by p300 temporally inhibits transcription during genotoxic stress response." Proceedings of the National Academy of Sciences 116, no. 44 (October 14, 2019): 22140–51. http://dx.doi.org/10.1073/pnas.1907097116.

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Soon after exposure to genotoxic reagents, mammalian cells inhibit transcription to prevent collisions with repair machinery and to mount a proper DNA damage response. However, mechanisms underlying early transcriptional inhibition are poorly understood. In this report, we show that site-specific acetylation of super elongation complex (SEC) subunit AFF1 by p300 reduces its interaction with other SEC components and impairs P-TEFb−mediated C-terminal domain phosphorylation of RNA polymerase II both in vitro and in vivo. Reexpression of wild-type AFF1, but not an acetylation mimic mutant, restores SEC component recruitment and target gene expression in AFF1 knockdown cells. Physiologically, we show that, upon genotoxic exposure, p300-mediated AFF1 acetylation is dynamic and strongly correlated with concomitant global down-regulation of transcription—and that this can be reversed by overexpression of an acetylation-defective AFF1 mutant. Therefore, we describe a mechanism of dynamic transcriptional regulation involving p300-mediated acetylation of a key elongation factor during genotoxic stress.

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Schwartz, Dov, and Varda Rotter. "p53-Dependent cell cycle control: response to genotoxic stress." Seminars in Cancer Biology 8, no. 5 (January 1998): 325–36. http://dx.doi.org/10.1006/scbi.1998.0095.

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Qin, Lili, Larry S. Wu, Ming Fan, and Jian Jian Li. "Enhanced Mitochondrial Bioenergetics in Genotoxic Stress Induced Adaptive Response." Free Radical Biology and Medicine 76 (November 2014): S151. http://dx.doi.org/10.1016/j.freeradbiomed.2014.10.566.

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Kasapi, Ana, and Antigoni Triantafyllopoulou. "Genotoxic stress signalling as a driver of macrophage diversity." Cell Stress 6, no. 3 (March 14, 2022): 30–44. http://dx.doi.org/10.15698/cst2022.03.265.

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Tissue macrophages arise from yolk sac, fetal liver and hematopoietic progenitors and adopt diverse transcriptional programs and phenotypes, instructed by their microenvironment. In chronic inflammation, such as in chronic infections, autoimmunity, or cancer, tissue microenvironments change dramatically thus imprinting new programs on tissue macrophages. While stress is a known driver of carcinogenesis in epithelial cells, emerging evidence suggests that macrophage responses to genotoxic stress are embedded in their ‘physiologic’ immune and tissue healing programs and in most cases do not lead to myeloid malignancies. The role of genotoxic stress as an instructor of macrophage-mediated immune defense and tissue remodeling is only beginning to be understood. Here, we review the evidence showing that genotoxic stress, which macrophages and their precursors face upon encountering inflammatory and/or growth signals, instructs their transcriptional programs, by activating non-canonical, cell-type specific DNA Damage Response (DDR)-driven signaling pathways. We propose that immune-cell specific, DDR-instructed programs are crucial for tissue homeostasis as well as for the maintenance and resolution of inflammatory responses in infection, cancer, autoinflammatory and autoimmune microenvironments.

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Nickoloff, Jac A. "Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy." Molecules 27, no. 15 (July 25, 2022): 4736. http://dx.doi.org/10.3390/molecules27154736.

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Proliferating cells regularly experience replication stress caused by spontaneous DNA damage that results from endogenous reactive oxygen species (ROS), DNA sequences that can assume secondary and tertiary structures, and collisions between opposing transcription and replication machineries. Cancer cells face additional replication stress, including oncogenic stress that results from the dysregulation of fork progression and origin firing, and from DNA damage induced by radiotherapy and most cancer chemotherapeutic agents. Cells respond to such stress by activating a complex network of sensor, signaling and effector pathways that protect genome integrity. These responses include slowing or stopping active replication forks, protecting stalled replication forks from collapse, preventing late origin replication firing, stimulating DNA repair pathways that promote the repair and restart of stalled or collapsed replication forks, and activating dormant origins to rescue adjacent stressed forks. Currently, most cancer patients are treated with genotoxic chemotherapeutics and/or ionizing radiation, and cancer cells can gain resistance to the resulting replication stress by activating pro-survival replication stress pathways. Thus, there has been substantial effort to develop small molecule inhibitors of key replication stress proteins to enhance tumor cell killing by these agents. Replication stress targets include ATR, the master kinase that regulates both normal replication and replication stress responses; the downstream signaling kinase Chk1; nucleases that process stressed replication forks (MUS81, EEPD1, Metnase); the homologous recombination catalyst RAD51; and other factors including ATM, DNA-PKcs, and PARP1. This review provides an overview of replication stress response pathways and discusses recent pre-clinical studies and clinical trials aimed at improving cancer therapy by targeting replication stress response factors.

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Reichard, John F., Timothy P. Dalton, Howard G. Shertzer, and Alvaro Puga. "Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor." Dose-Response 3, no. 3 (May 1, 2005): dose—response.0. http://dx.doi.org/10.2203/dose-response.003.03.003.

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TCDD and other polyhalogenated aromatic hydrocarbon ligands of the aryl hydrocarbon receptor (AHR) have been classically considered as non-genotoxic compounds because they fail to be directly mutagenic in either bacteria or most in vitro assay systems. They do so in spite of having repeatedly been linked to oxidative stress and to mutagenic and carcinogenic outcomes. Oxidative stress, on the other hand, has been used as a marker for the toxicity of dioxin and its congeners. We have focused this review on the connection between oxidative stress induction and the toxic effects of fetal and adult dioxin exposure, with emphasis on the large species difference in sensitivity to this agent. We examine the roles that the dioxin-inducible cytochromes P450s play in the cellular and toxicological consequences of dioxin exposure with emphasis on oxidative stress involvement. Many components of the health consequences resulting from dioxin exposure may be attributable to epigenetic mechanisms arising from prolonged reactive oxygen generation.

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Oda, Tsukasa, Toshiya Hayano, Hidenobu Miyaso, Nobuhiro Takahashi, and Takayuki Yamashita. "Hsp90 regulates the Fanconi anemia DNA damage response pathway." Blood 109, no. 11 (June 1, 2007): 5016–26. http://dx.doi.org/10.1182/blood-2006-08-038638.

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Abstract Heat shock protein 90 (Hsp90) regulates diverse signaling pathways. Emerging evidence suggests that Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), enhance DNA damage-induced cell death, suggesting that Hsp90 may regulate cellular responses to genotoxic stress. However, the underlying mechanisms are poorly understood. Here, we show that the Fanconi anemia (FA) pathway is involved in the Hsp90-mediated regulation of genotoxic stress response. In the FA pathway, assembly of 8 FA proteins including FANCA into a nuclear multiprotein complex, and the complex-dependent activation of FANCD2 are critical events for cellular tolerance against DNA cross-linkers. Hsp90 associates with FANCA, in vivo and in vitro, in a 17-AAG–sensitive manner. Disruption of the FANCA/Hsp90 association by cellular treatment with 17-AAG induces rapid proteasomal degradation and cytoplasmic relocalization of FANCA, leading to impaired activation of FANCD2. Furthermore, 17-AAG promotes DNA cross-linker–induced cytotoxicity, but this effect is much less pronounced in FA pathway-defective cells. Notably, 17-AAG enhances DNA cross-linker–induced chromosome aberrations. In conclusion, our results identify FANCA as a novel client of Hsp90, suggesting that Hsp90 promotes activation of the FA pathway through regulation of intracellular turnover and trafficking of FANCA, which is critical for cellular tolerance against genotoxic stress.

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Liu, Li, and David E. Levin. "Intracellular mechanism by which genotoxic stress activates yeast SAPK Mpk1." Molecular Biology of the Cell 29, no. 23 (November 15, 2018): 2898–909. http://dx.doi.org/10.1091/mbc.e18-07-0441.

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Stress-activated MAP kinases (SAPKs) respond to a wide variety of stressors. In most cases, the pathways through which specific stress signals are transmitted to the SAPKs are not known. The Saccharomyces cerevisiae SAPK Mpk1 (Slt2) is a well-characterized component of the cell-wall integrity (CWI) signaling pathway, which responds to physical and chemical challenges to the cell wall. However, Mpk1 is also activated in response to genotoxic stress through an unknown pathway. We show that, in contrast to cell-wall stress, the pathway for Mpk1 activation by genotoxic stress does not involve the stimulation of the MAP kinase kinases (MEKs) that function immediately upstream of Mpk1. Instead, DNA damage activates Mpk1 through induction of proteasomal degradation of Msg5, the dual-specificity protein phosphatase principally responsible for maintaining Mpk1 in a low-activity state in the absence of stress. Blocking Msg5 degradation in response to genotoxic stress prevented Mpk1 activation. This work raises the possibility that other Mpk1-activating stressors act intracellularly at different points along the canonical Mpk1 activation pathway.

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Hossain, Mohammad B., Rehnuma Shifat, David G. Johnson, Mark T. Bedford, Konrad R. Gabrusiewicz, Nahir Cortes-Santiago, Xuemei Luo, et al. "TIE2-mediated tyrosine phosphorylation of H4 regulates DNA damage response by recruiting ABL1." Science Advances 2, no. 4 (April 2016): e1501290. http://dx.doi.org/10.1126/sciadv.1501290.

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DNA repair pathways enable cancer cells to survive DNA damage induced after genotoxic therapies. Tyrosine kinase receptors (TKRs) have been reported as regulators of the DNA repair machinery. TIE2 is a TKR overexpressed in human gliomas at levels that correlate with the degree of increasing malignancy. Following ionizing radiation, TIE2 translocates to the nucleus, conferring cells with an enhanced nonhomologous end-joining mechanism of DNA repair that results in a radioresistant phenotype. Nuclear TIE2 binds to key components of DNA repair and phosphorylates H4 at tyrosine 51, which, in turn, is recognized by the proto-oncogene ABL1, indicating a role for nuclear TIE2 as a sensor for genotoxic stress by action as a histone modifier. H4Y51 constitutes the first tyrosine phosphorylation of core histones recognized by ABL1, defining this histone modification as a direct signal to couple genotoxic stress with the DNA repair machinery.

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Stultz, Laura K., Alexandra Hunsucker, Sydney Middleton, Evan Grovenstein, Jacob O’Leary, Eliot Blatt, Mary Miller, James Mobley, and Pamela K. Hanson. "Proteomic analysis of the S. cerevisiae response to the anticancer ruthenium complex KP1019." Metallomics 12, no. 6 (2020): 876–90. http://dx.doi.org/10.1039/d0mt00008f.

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Roa, Hélène, Julien Lang, Kevin M. Culligan, Murielle Keller, Sarah Holec, Valérie Cognat, Marie-Hélène Montané, Guy Houlné, and Marie-Edith Chabouté. "Ribonucleotide Reductase Regulation in Response to Genotoxic Stress in Arabidopsis." Plant Physiology 151, no. 1 (July 1, 2009): 461–71. http://dx.doi.org/10.1104/pp.109.140053.

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Fritz, Gerhard, Sabine Grösch, Maja Tomicic, and Bernd Kaina. "APE/Ref-1 and the mammalian response to genotoxic stress." Toxicology 193, no. 1-2 (November 2003): 67–78. http://dx.doi.org/10.1016/s0300-483x(03)00290-7.

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Itakura, Eisuke, Kazuyuki Umeda, Ei Sekoguchi, Hideki Takata, Mariko Ohsumi, and Akira Matsuura. "ATR-dependent phosphorylation of ATRIP in response to genotoxic stress." Biochemical and Biophysical Research Communications 323, no. 4 (October 2004): 1197–202. http://dx.doi.org/10.1016/j.bbrc.2004.08.228.

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Liebermann, Dan A., and Barbara Hoffman. "Gadd45 in the response of hematopoietic cells to genotoxic stress." Blood Cells, Molecules, and Diseases 39, no. 3 (November 2007): 329–35. http://dx.doi.org/10.1016/j.bcmd.2007.06.006.

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Weiss, Robert S., Philip Leder, and Cyrus Vaziri. "Critical Role for Mouse Hus1 in an S-Phase DNA Damage Cell Cycle Checkpoint." Molecular and Cellular Biology 23, no. 3 (February 1, 2003): 791–803. http://dx.doi.org/10.1128/mcb.23.3.791-803.2003.

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ABSTRACT Mouse Hus1 encodes an evolutionarily conserved DNA damage response protein. In this study we examined how targeted deletion of Hus1 affects cell cycle checkpoint responses to genotoxic stress. Unlike hus1− fission yeast (Schizosaccharomyces pombe) cells, which are defective for the G2/M DNA damage checkpoint, Hus1-null mouse cells did not inappropriately enter mitosis following genotoxin treatment. However, Hus1-deficient cells displayed a striking S-phase DNA damage checkpoint defect. Whereas wild-type cells transiently repressed DNA replication in response to benzo(a)pyrene dihydrodiol epoxide (BPDE), a genotoxin that causes bulky DNA adducts, Hus1-null cells maintained relatively high levels of DNA synthesis following treatment with this agent. However, when treated with DNA strand break-inducing agents such as ionizing radiation (IR), Hus1-deficient cells showed intact S-phase checkpoint responses. Conversely, checkpoint-mediated inhibition of DNA synthesis in response to BPDE did not require NBS1, a component of the IR-responsive S-phase checkpoint pathway. Taken together, these results demonstrate that Hus1 is required specifically for one of two separable mammalian checkpoint pathways that respond to distinct forms of genome damage during S phase.

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Koczor, Christopher A., Aaron J. Haider, Kate M. Saville, Jianfeng Li, Joel F. Andrews, Alison V. Beiser, and Robert W. Sobol. "Live Cell Detection of Poly(ADP-Ribose) for Use in Genetic and Genotoxic Compound Screens." Cancers 14, no. 15 (July 28, 2022): 3676. http://dx.doi.org/10.3390/cancers14153676.

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Poly(ADP-ribose) (PAR) is a molecular scaffold that aids in the formation of DNA repair protein complexes. Tools to sensitively quantify PAR in live cells have been lacking. We recently described the LivePAR probe (EGFP fused to the RNF146-encoded WWE PAR binding domain) to measure PAR formation at sites of laser micro-irradiation in live cells. Here, we present two methods that expand on the use of LivePAR and its WWE domain. First, LivePAR enriches in the nucleus of cells following genotoxic challenge. Image quantitation can identify single-cell PAR formation following genotoxic stress at concentrations lower than PAR ELISA or PAR immunoblot, with greater sensitivity to genotoxic stress than CometChip. In a second approach, we used the RNF146-encoded WWE domain to develop a split luciferase probe for analysis in a 96-well plate assay. We then applied these PAR analysis tools to demonstrate their broad applicability. First, we show that both approaches can identify genetic modifications that alter PARylation levels, such as hyper-PARylation in BRCA2-deficient cancer cells. Second, we demonstrate the utility of the WWE split luciferase assay to characterize the cellular response of genotoxins, PARP inhibitors, and PARG inhibitors, thereby providing a screening method to identify PAR modulating compounds.

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Yoshida, Kiyotsugu, Tomoko Yamaguchi, Hirokuni Shinagawa, Naoe Taira, Keiichi I. Nakayama, and Yoshio Miki. "Protein Kinase C δ Activates Topoisomerase IIα To Induce Apoptotic Cell Death in Response to DNA Damage." Molecular and Cellular Biology 26, no. 9 (May 1, 2006): 3414–31. http://dx.doi.org/10.1128/mcb.26.9.3414-3431.2006.

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ABSTRACT DNA topoisomerase II is an essential nuclear enzyme that modulates DNA processes by altering the topological state of double-stranded DNA. This enzyme is required for chromosome condensation and segregation; however, the regulatory mechanism of its activation is largely unknown. Here we demonstrate that topoisomerase IIα is activated in response to genotoxic stress. Concomitant with the activation, the expression of topoisomerase IIα is increased following DNA damage. The results also demonstrate that the proapoptotic kinase protein kinase C δ (PKCδ) interacts with topoisomerase IIα. This association is in an S-phase-specific manner and is required for stabilization and catalytic activation of topoisomerase IIα in response to DNA damage. Conversely, inhibition of PKCδ activity attenuates DNA damage-induced activation of topoisomerase IIα. Finally, aberrant activation of topoisomerase IIα by PKCδ is associated with induction of apoptosis upon exposure to genotoxic agents. These findings indicate that PKCδ regulates topoisomerase IIα and thereby cell fate in the genotoxic stress response.

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Zellweger, Ralph, Damian Dalcher, Karun Mutreja, Matteo Berti, Jonas A. Schmid, Raquel Herrador, Alessandro Vindigni, and Massimo Lopes. "Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells." Journal of Cell Biology 208, no. 5 (March 2, 2015): 563–79. http://dx.doi.org/10.1083/jcb.201406099.

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Replication fork reversal protects forks from breakage after poisoning of Topoisomerase 1. We here investigated fork progression and chromosomal breakage in human cells in response to a panel of sublethal genotoxic treatments, using other topoisomerase poisons, DNA synthesis inhibitors, interstrand cross-linking inducers, and base-damaging agents. We used electron microscopy to visualize fork architecture under these conditions and analyzed the association of specific molecular features with checkpoint activation. Our data identify replication fork uncoupling and reversal as global responses to genotoxic treatments. Both events are frequent even after mild treatments that do not affect fork integrity, nor activate checkpoints. Fork reversal was found to be dependent on the central homologous recombination factor RAD51, which is consistently present at replication forks independently of their breakage, and to be antagonized by poly (ADP-ribose) polymerase/RECQ1-regulated restart. Our work establishes remodeling of uncoupled forks as a pivotal RAD51-regulated response to genotoxic stress in human cells and as a promising target to potentiate cancer chemotherapy.

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von Stechow, Louise, Dimitris Typas, Jordi Carreras Puigvert, Laurens Oort, Ramakrishnaiah Siddappa, Alex Pines, Harry Vrieling, Bob van de Water, Leon H. F. Mullenders, and Erik H. J. Danen. "The E3 Ubiquitin Ligase ARIH1 Protects against Genotoxic Stress by Initiating a 4EHP-Mediated mRNA Translation Arrest." Molecular and Cellular Biology 35, no. 7 (January 26, 2015): 1254–68. http://dx.doi.org/10.1128/mcb.01152-14.

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DNA damage response signaling is crucial for genome maintenance in all organisms and is corrupted in cancer. In an RNA interference (RNAi) screen for (de)ubiquitinases and sumoylases modulating the apoptotic response of embryonic stem (ES) cells to DNA damage, we identified the E3 ubiquitin ligase/ISGylase, ariadne homologue 1 (ARIH1). Silencing ARIH1 sensitized ES and cancer cells to genotoxic compounds and ionizing radiation, irrespective of their p53 or caspase-3 status. Expression of wild-type but not ubiquitinase-defective ARIH1 constructs prevented sensitization caused by ARIH1 knockdown. ARIH1 protein abundance increased after DNA damage through attenuation of proteasomal degradation that required ATM signaling. Accumulated ARIH1 associated with 4EHP, and in turn, this competitive inhibitor of the eukaryotic translation initiation factor 4E (eIF4E) underwent increased nondegradative ubiquitination upon DNA damage. Genotoxic stress led to an enrichment of ARIH1 in perinuclear, ribosome-containing regions and triggered 4EHP association with the mRNA 5′ cap as well as mRNA translation arrest in an ARIH1-dependent manner. Finally, restoration of DNA damage-induced translation arrest in ARIH1-depleted cells by means of an eIF2 inhibitor was sufficient to reinstate resistance to genotoxic stress. These findings identify ARIH1 as a potent mediator of DNA damage-induced translation arrest that protects stem and cancer cells against genotoxic stress.

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Jeong, Yeon-Tae, Mario Rossi, Lukas Cermak, Anita Saraf, Laurence Florens, Michael P. Washburn, Patrick Sung, Carl L. Schildkraut, and Michele Pagano. "FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress." Journal of Cell Biology 200, no. 2 (January 14, 2013): 141–49. http://dx.doi.org/10.1083/jcb.201209002.

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Proper resolution of stalled replication forks is essential for genome stability. Purification of FBH1, a UvrD DNA helicase, identified a physical interaction with replication protein A (RPA), the major cellular single-stranded DNA (ssDNA)–binding protein complex. Compared with control cells, FBH1-depleted cells responded to replication stress with considerably fewer double-strand breaks (DSBs), a dramatic reduction in the activation of ATM and DNA-PK and phosphorylation of RPA2 and p53, and a significantly increased rate of survival. A minor decrease in ssDNA levels was also observed. All these phenotypes were rescued by wild-type FBH1, but not a FBH1 mutant lacking helicase activity. FBH1 depletion had no effect on other forms of genotoxic stress in which DSBs form by means that do not require ssDNA intermediates. In response to catastrophic genotoxic stress, apoptosis prevents the persistence and propagation of DNA lesions. Our findings show that FBH1 helicase activity is required for the efficient induction of DSBs and apoptosis specifically in response to DNA replication stress.

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Herzberg, Kristina, Vladimir I. Bashkirov, Michael Rolfsmeier, Edwin Haghnazari, W. Hayes McDonald, Scott Anderson, Elena V. Bashkirova, John R. Yates, and Wolf-Dietrich Heyer. "Phosphorylation of Rad55 on Serines 2, 8, and 14 Is Required for Efficient Homologous Recombination in the Recovery of Stalled Replication Forks." Molecular and Cellular Biology 26, no. 22 (September 11, 2006): 8396–409. http://dx.doi.org/10.1128/mcb.01317-06.

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ABSTRACT DNA damage checkpoints coordinate the cellular response to genotoxic stress and arrest the cell cycle in response to DNA damage and replication fork stalling. Homologous recombination is a ubiquitous pathway for the repair of DNA double-stranded breaks and other checkpoint-inducing lesions. Moreover, homologous recombination is involved in postreplicative tolerance of DNA damage and the recovery of DNA replication after replication fork stalling. Here, we show that the phosphorylation on serines 2, 8, and 14 (S2,8,14) of the Rad55 protein is specifically required for survival as well as for normal growth under genome-wide genotoxic stress. Rad55 is a Rad51 paralog in Saccharomyces cerevisiae and functions in the assembly of the Rad51 filament, a central intermediate in recombinational DNA repair. Phosphorylation-defective rad55-S2,8,14A mutants display a very slow traversal of S phase under DNA-damaging conditions, which is likely due to the slower recovery of stalled replication forks or the slower repair of replication-associated DNA damage. These results suggest that Rad55-S2,8,14 phosphorylation activates recombinational repair, allowing for faster recovery after genotoxic stress.

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Mohanan, Gayatri, Amiyaranjan Das, and Purusharth I. Rajyaguru. "Genotoxic stress response: What is the role of cytoplasmic mRNA fate?" BioEssays 43, no. 8 (June 7, 2021): 2000311. http://dx.doi.org/10.1002/bies.202000311.

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Vinson, R. K. "Genotoxic Stress Response Gene Expression in the Mid-Organogenesis Rat Conceptus." Toxicological Sciences 74, no. 1 (May 2, 2003): 157–64. http://dx.doi.org/10.1093/toxsci/kfg097.

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Gao, Jiaxin, Haitao Wang, Ada Hang-Heng Wong, Guisheng Zeng, Zhenxing Huang, Yanming Wang, Jianli Sang, and Yue Wang. "Regulation of Rfa2 phosphorylation in response to genotoxic stress inCandida albicans." Molecular Microbiology 94, no. 1 (August 21, 2014): 141–55. http://dx.doi.org/10.1111/mmi.12749.

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Fritsch, C., J. F. Gout, S. Haroon, A. Towheed, C. Chung, J. LaGosh, E. McGann, et al. "Genome-wide surveillance of transcription errors in response to genotoxic stress." Proceedings of the National Academy of Sciences 118, no. 1 (December 21, 2020): e2004077118. http://dx.doi.org/10.1073/pnas.2004077118.

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Mutagenic compounds are a potent source of human disease. By inducing genetic instability, they can accelerate the evolution of human cancers or lead to the development of genetically inherited diseases. Here, we show that in addition to genetic mutations, mutagens are also a powerful source of transcription errors. These errors arise in dividing and nondividing cells alike, affect every class of transcripts inside cells, and, in certain cases, greatly exceed the number of mutations that arise in the genome. In addition, we reveal the kinetics of transcription errors in response to mutagen exposure and find that DNA repair is required to mitigate transcriptional mutagenesis after exposure. Together, these observations have far-reaching consequences for our understanding of mutagenesis in human aging and disease, and suggest that the impact of DNA damage on human physiology has been greatly underestimated.

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Colman, Michael S., Cynthia A. Afshari, and J. Carl Barrett. "Regulation of p53 stability and activity in response to genotoxic stress." Mutation Research/Reviews in Mutation Research 462, no. 2-3 (April 2000): 179–88. http://dx.doi.org/10.1016/s1383-5742(00)00035-1.

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Park, Soo-Yeon, Hyo-Kyoung Choi, Seong-Ho Jo, JaeSung Seo, Eun-Jeong Han, Kyung-Chul Choi, Jae-Wook Jeong, Youngsok Choi, and Ho-Geun Yoon. "YAF2 promotes TP53-mediated genotoxic stress response via stabilization of PDCD5." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1853, no. 5 (May 2015): 1060–72. http://dx.doi.org/10.1016/j.bbamcr.2015.01.006.

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Lezina, Larissa, Vasilisa Aksenova, Olga Fedorova, Daria Malikova, Oleg Shuvalov, Alexey V. Antonov, Dmitri Tentler, Alexander V. Garabadgiu, Gerry Melino, and Nikolai A. Barlev. "KMT Set7/9 affects genotoxic stress response via the Mdm2 axis." Oncotarget 6, no. 28 (August 1, 2015): 25843–55. http://dx.doi.org/10.18632/oncotarget.4584.

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WANG, Jean Y. J. "Nucleo-cytoplasmic communication in apoptotic response to genotoxic and inflammatory stress." Cell Research 15, no. 1 (January 2005): 43–48. http://dx.doi.org/10.1038/sj.cr.7290263.

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Fortunato, Rodrigo S., Luciana R. Gomes, Veridiana Munford, Carolina Fittipaldi Pessoa, Annabel Quinet, Fabio Hecht, Gustavo S. Kajitani, Cristiane Bedran Milito, Denise P. Carvalho, and Carlos Frederico Martins Menck. "DUOX1 Silencing in Mammary Cell Alters the Response to Genotoxic Stress." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–9. http://dx.doi.org/10.1155/2018/3570526.

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DUOX1 is an H2O2-generating enzyme related to a wide range of biological features, such as hormone synthesis, host defense, cellular proliferation, and fertilization. DUOX1 is frequently downregulated in lung and liver cancers, suggesting a tumor suppressor role for this enzyme. Here, we show that DUOX1 expression is decreased in breast cancer cell lines and also in breast cancers when compared to the nontumor counterpart. In order to address the role of DUOX1 in breast cells, we stably knocked down the expression of DUOX1 in nontumor mammary cells (MCF12A) with shRNA. This led to higher cell proliferation rates and decreased migration and adhesion properties, which are typical features for transformed cells. After genotoxic stress induced by doxorubicin, DUOX1-silenced cells showed reduced IL-6 and IL-8 secretion and increased apoptosis levels. Furthermore, the cell proliferation rate was higher in DUOX1-silenced cells after doxorubicin medication in comparison to control cells. In conclusion, we demonstrate here that DUOX1 is silenced in breast cancer, which seems to be involved in breast carcinogenesis.

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Chwee, Jyh Yun, Muznah Khatoo, Nikki Yi Jie Tan, and Stephan Gasser. "Apoptotic Cells Release IL1 Receptor Antagonist in Response to Genotoxic Stress." Cancer Immunology Research 4, no. 4 (February 12, 2016): 294–302. http://dx.doi.org/10.1158/2326-6066.cir-15-0083.

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Fionda, Cinzia, Danilo Di Bona, Andrea Kosta, Helena Stabile, Angela Santoni, and Marco Cippitelli. "The POU-Domain Transcription Factor Oct-6/POU3F1 as a Regulator of Cellular Response to Genotoxic Stress." Cancers 11, no. 6 (June 11, 2019): 810. http://dx.doi.org/10.3390/cancers11060810.

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DNA damage and the generation of reactive oxygen species (ROS) are key mechanisms of apoptotic cell death by commonly used genotoxic drugs. However, the complex cellular response to these pharmacologic agents remains yet to be fully characterized. Several studies have described the role of transcription factor octamer-1 (Oct-1)/Pit-1, Oct-1/2, and Unc-86 shared domain class 2 homeobox 1 (POU2F1) in the regulation of the genes important for cellular response to genotoxic stress. Evaluating the possible involvement of other POU family transcription factors in these pathways, we revealed the inducible expression of Oct-6/POU3F1, a regulator of neural morphogenesis and epidermal differentiation, in cancer cells by genotoxic drugs. The induction of Oct-6 occurs at the transcriptional level via reactive oxygen species (ROS) and ataxia telangiectasia mutated- and Rad3-related (ATR)-dependent mechanisms, but in a p53 independent manner. Moreover, we provide evidence that Oct-6 may play a role in the regulation of cellular response to DNA damaging agents. Indeed, by using the shRNA approach, we demonstrate that in doxorubicin-treated H460 non-small-cell lung carcinoma (NSCLC) cells, Oct-6 depletion leads to a reduced G2-cell cycle arrest and senescence, but also to increased levels of intracellular ROS and DNA damage. In addition, we could identify p21 and catalase as Oct-6 target genes possibly mediating these effects. These results demonstrate that Oct-6 is expressed in cancer cells after genotoxic stress, and suggests its possible role in the control of ROS, DNA damage response (DDR), and senescence.

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Evdokimov, Alexey, Irina Petruseva, Aleksei Popov, Olga Koval, and Olga Lavrik. "Naked mole rat cells display more efficient DNA excision repair and higher resistance to toxic impacts than mouse cells." BIO Web of Conferences 22 (2020): 01017. http://dx.doi.org/10.1051/bioconf/20202201017.

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Naked mole rat is the long-lived and tumor-resistant rodent. Naked mole rat possesses multiple adaptations that may contribute to longevity and cancer-resistance. Higher activity of DNA excision repair systems and their faster recovery after genotoxic impact as compare with Mus musculus directly demonstrated in our previous investigation contribute to longevity and cancer resistance of naked mole rat. In the present study the DNA-damage-induced apoptosis in naked mole rat fibroblasts was studied using conventional methods. The ability of naked mole rat cells to undergo regulated cell death in response to genotoxic stress is another group of cell defense mechanisms. Naked mole rat skin fibroblasts were demonstrated to be much more resistant towards proapoptotic reagents methyl methanesulfonate, 5-fluorouracil and etoposide as compared with fibroblasts of Mus musculus. Naked mole rat cells have demonstrated limited apoptotic response and seem to undergo also other-type regulated cell death under severe genotoxic stress.

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Byrum, Jennifer, William Rodgers, and Karla Rodgers. "Elucidating regulatory mechanisms of RAG2 in response to DNA damage." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 204.10. http://dx.doi.org/10.4049/jimmunol.196.supp.204.10.

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Abstract V(D)J recombination of lymphocyte antigen receptor genes occurs via the formation of DNA double strand breaks (DSBs) through the activity of RAG1 and RAG2. The co-existence of RAG-independent DNA DSBs generated by genotoxic stressors potentially increases the risk of incorrect repair and chromosomal abnormalities. However, it is not known whether cellular responses to DSBs by genotoxic stressors affect the RAG complex. Using cellular imaging and subcellular fractionation approaches, we show that formation of DSBs by treating cells with DNA damaging agents causes export of nuclear RAG2. Within the cytoplasm, RAG2 exhibited substantial enrichment at the centrosome. Further, RAG2 export was sensitive to inhibition of ATM, and was reversed following DNA repair. Live cell imaging reveals export of RAG2 within minutes of DNA damage, demonstrating a rapid response to genotoxic stress. Intriguingly, dose response assessment exhibited RAG2 export following the generation of very few DNA DSBs, indicating that DNA damage-triggered export of RAG2 can occur under normal physiological conditions. The core region of RAG2 was sufficient for export, but not centrosome targeting, and RAG2 export was blocked by mutation of Thr490. In summary, DNA damage triggers relocalization of RAG2 from the nucleus to centrosomes, suggesting a novel mechanism for modulation of cellular responses to DSBs in developing lymphocytes.

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Buch-Larsen, Sara C., Alexandra K. L. F. S. Rebak, Ivo A. Hendriks, and Michael L. Nielsen. "Temporal and Site-Specific ADP-Ribosylation Dynamics upon Different Genotoxic Stresses." Cells 10, no. 11 (October 28, 2021): 2927. http://dx.doi.org/10.3390/cells10112927.

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The DNA damage response revolves around transmission of information via post-translational modifications, including reversible protein ADP-ribosylation. Here, we applied a mass-spectrometry-based Af1521 enrichment technology for the identification and quantification of ADP-ribosylation sites as a function of various DNA damage stimuli and time. In total, we detected 1681 ADP-ribosylation sites residing on 716 proteins in U2OS cells and determined their temporal dynamics after exposure to the genotoxins H2O2 and MMS. Intriguingly, we observed a widespread but low-abundance serine ADP-ribosylation response at the earliest time point, with later time points centered on increased modification of the same sites. This suggests that early serine ADP-ribosylation events may serve as a platform for an integrated signal response. While treatment with H2O2 and MMS induced homogenous ADP-ribosylation responses, we observed temporal differences in the ADP-ribosylation site abundances. Exposure to MMS-induced alkylating stress induced the strongest ADP-ribosylome response after 30 min, prominently modifying proteins involved in RNA processing, whereas in response to H2O2-induced oxidative stress ADP-ribosylation peaked after 60 min, mainly modifying proteins involved in DNA damage pathways. Collectively, the dynamic ADP-ribosylome presented here provides a valuable insight into the temporal cellular regulation of ADP-ribosylation in response to DNA damage.

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Shen, Changxian, Cynthia S. Lancaster, Bin Shi, Hong Guo, Padma Thimmaiah, and Mary-Ann Bjornsti. "TOR Signaling Is a Determinant of Cell Survival in Response to DNA Damage." Molecular and Cellular Biology 27, no. 20 (August 13, 2007): 7007–17. http://dx.doi.org/10.1128/mcb.00290-07.

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ABSTRACT The conserved TOR (target of rapamycin) kinase is part of a TORC1 complex that regulates cellular responses to environmental stress, such as amino acid starvation and hypoxia. Dysregulation of Akt-TOR signaling has also been linked to the genesis of cancer, and thus, this pathway presents potential targets for cancer chemotherapeutics. Here we report that rapamycin-sensitive TORC1 signaling is required for the S-phase progression and viability of yeast cells in response to genotoxic stress. In the presence of the DNA-damaging agent methyl methanesulfonate (MMS), TOR-dependent cell survival required a functional S-phase checkpoint. Rapamycin inhibition of TORC1 signaling suppressed the Rad53 checkpoint-mediated induction of ribonucleotide reductase subunits Rnr1 and Rnr3, thereby abrogating MMS-induced mutagenesis and enhancing cell lethality. Moreover, cells deleted for RNR3 were hypersensitive to rapamycin plus MMS, providing the first demonstration that Rnr3 contributes to the survival of cells exposed to DNA damage. Our findings support a model whereby TORC1 acts as a survival pathway in response to genotoxic stress by maintaining the deoxynucleoside triphosphate pools necessary for error-prone translesion DNA polymerases. Thus, TOR-dependent cell survival in response to DNA-damaging agents coincides with increased mutation rates, which may contribute to the acquisition of chemotherapeutic drug resistance.

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Guzman, Monica L., Xiaojie Li, Cheryl Corbett, Duane C. Hassane, and Craig T. Jordan. "Mechanisms Controlling Selective Death of Leukemia Stem Cells in Response to Parthenolide." Blood 106, no. 11 (November 16, 2005): 467. http://dx.doi.org/10.1182/blood.v106.11.467.467.

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Abstract Studies have shown that human acute myelogenous leukemia (AML) originates from a rare population of leukemic stem cells (LSCs). LSCs are found in nearly all AML subtypes and are sufficient to initiate and maintain leukemic growth in both long-term cultures and NOD/SCID mice. Since conventional chemotherapy drugs typically target actively cycling leukemic blast cells, the quiescent LSC population is likely to be drug resistant. Recently, we have described agents that can selectively kill LSC while sparing normal hematopoietic stem cells (HSC), thus demonstrating that quiescent LSC can be effectively destroyed. In particular, the sesquiterpene lactone parthenolide (PTL) is active as a single agent and can induce robust LSC-specific apoptosis. Therefore, we sought to further elucidate the mechanisms that result in leukemia-specific death. To this end, we have shown that PTL inhibits NF- κB and activates p53 in AML cells. Moreover, we have found that AML cells are highly-oxidized relative to their normal less-oxidized counterparts as determined by dihydrofluorescein diacetate (H2DCF-DA) fluorescence. Although PTL treatment was found to increase the basal oxidative load of both normal and leukemic cells, these increases were ultimately associated with only leukemia-specific death. High levels of reactive oxygen species are associated with genotoxic stress. Therefore, we hypothesized that PTL-mediated increases of the oxidative load in AML cells would be sufficient to produce genotoxic stress in AML cells, but not normal cells. We thus examined pathways involved in sensing and responding to oxidative and genotoxic stress. These studies demonstrate that upon PTL treatment, AML cells phosphorylate p53 on serine 15, and increase transcription of several downstream p53 pro-apoptotic genes, including GADD45, Bax, and p21. In addition, we detected phosphorylation of ATM on serine 1981, γ-H2AX, and phosphorylation of Chk2 on threonine 68. Importantly, these events are not observed in normal hematopoietic cells treated with PTL. These findings suggest a DNA damage/repair response to PTL in AML cells, and that normal cells appear to be resistant to this mechanism. Collectively, these data indicate that oxidative stress and DNA damage pathways may be a central component of PTL-induced apoptosis. We propose a model whereby AML cells exist in a physiological state in which PTL is able to preferentially invoke genotoxic stress in AML. Based on empirical evidence, we suggest that AML LSC also exist in such a state, and that PTL mediated inhibition of NF- κB and induction of stress leads to selective apoptosis of malignant cells, sparing normal cell populations.

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Kharbanda, Surender, Pramod Pandey, Teruo Yamauchi, Shailender Kumar, Masao Kaneki, Vijay Kumar, Ajit Bharti, et al. "Activation of MEK Kinase 1 by the c-Abl Protein Tyrosine Kinase in Response to DNA Damage." Molecular and Cellular Biology 20, no. 14 (July 15, 2000): 4979–89. http://dx.doi.org/10.1128/mcb.20.14.4979-4989.2000.

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ABSTRACT The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents and regulates induction of the stress-activated c-Jun N-terminal protein kinase (SAPK). Here we show that nuclear c-Abl associates with MEK kinase 1 (MEKK-1), an upstream effector of the SEK1→SAPK pathway, in the response of cells to genotoxic stress. The results demonstrate that the nuclear c-Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vivo. Transient-transfection studies with wild-type and kinase-inactive c-Abl demonstrate c-Abl kinase-dependent activation of MEKK-1. Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage. The results also demonstrate that c-Abl induces MEKK-1-mediated phosphorylation and activation of SEK1-SAPK in coupled kinase assays. These findings indicate that c-Abl functions upstream of MEKK-1-dependent activation of SAPK in the response to genotoxic stress.

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Broadus, Matthew R., and Kathleen L. Gould. "Multiple protein kinases influence the redistribution of fission yeast Clp1/Cdc14 phosphatase upon genotoxic stress." Molecular Biology of the Cell 23, no. 20 (October 15, 2012): 4118–28. http://dx.doi.org/10.1091/mbc.e12-06-0475.

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The Cdc14 phosphatase family antagonizes Cdk1 phosphorylation and is important for mitotic exit. To access their substrates, Cdc14 phosphatases are released from nucleolar sequestration during mitosis. Clp1/Flp1, the Schizosaccharomyces pombe Cdc14 orthologue, and Cdc14B, a mammalian orthologue, also exit the nucleolus during interphase upon DNA replication stress or damage, respectively, implicating Cdc14 phosphatases in the response to genotoxic insults. However, a mechanistic understanding of Cdc14 phosphatase nucleolar release under these conditions is incomplete. We show here that relocalization of Clp1 during genotoxic stress is governed by complex phosphoregulation. Specifically, the Rad3 checkpoint effector kinases Cds1 and/or Chk1, the cell wall integrity mitogen-activated protein kinase Pmk1, and the cell cycle kinase Cdk1 directly phosphorylate Clp1 to promote genotoxic stress–induced nucleoplasmic accumulation. However, Cds1 and/or Chk1 phosphorylate RxxS sites preferentially upon hydroxyurea treatment, whereas Pmk1 and Cdk1 preferentially phosphorylate Clp1 TP sites upon H2O2 treatment. Abolishing both Clp1 RxxS and TP phosphosites eliminates any genotoxic stress–induced redistribution. Reciprocally, preventing dephosphorylation of Clp1 TP sites shifts the distribution of the enzyme to the nucleoplasm constitutively. This work advances our understanding of pathways influencing Clp1 localization and may provide insight into mechanisms controlling Cdc14B phosphatases in higher eukaryotes.

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Takatsuka, Hirotomo, Atsushi Shibata, and Masaaki Umeda. "Genome Maintenance Mechanisms at the Chromatin Level." International Journal of Molecular Sciences 22, no. 19 (September 27, 2021): 10384. http://dx.doi.org/10.3390/ijms221910384.

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Genome integrity is constantly threatened by internal and external stressors, in both animals and plants. As plants are sessile, a variety of environment stressors can damage their DNA. In the nucleus, DNA twines around histone proteins to form the higher-order structure “chromatin”. Unraveling how chromatin transforms on sensing genotoxic stress is, thus, key to understanding plant strategies to cope with fluctuating environments. In recent years, accumulating evidence in plant research has suggested that chromatin plays a crucial role in protecting DNA from genotoxic stress in three ways: (1) changes in chromatin modifications around damaged sites enhance DNA repair by providing a scaffold and/or easy access to DNA repair machinery; (2) DNA damage triggers genome-wide alterations in chromatin modifications, globally modulating gene expression required for DNA damage response, such as stem cell death, cell-cycle arrest, and an early onset of endoreplication; and (3) condensed chromatin functions as a physical barrier against genotoxic stressors to protect DNA. In this review, we highlight the chromatin-level control of genome stability and compare the regulatory systems in plants and animals to find out unique mechanisms maintaining genome integrity under genotoxic stress.

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Gao, Meili, Yongfei Li, Aqun Zheng, Xiaochang Xue, Lan Chen, and Yu Kong. "Lymphocyte Oxidative Stress/Genotoxic Effects Are Related to Serum IgG and IgA Levels in Coke Oven Workers." Scientific World Journal 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/801346.

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We investigated oxidative stress/genotoxic effects levels, immunoglobulin levels, polycyclic aromatic hydrocarbons (PAHs) levels exposed in 126 coke oven workers and in 78 control subjects, and evaluated the association between oxidative stress/genotoxic effects levels and immunoglobulin levels. Significant differences were observed in biomarkers, including 1-hydroxypyrene levels, employment time, percentages of alcohol drinkers, MDA, 8-OHdG levels, CTL levels and CTM, MN, CA frequency, and IgG, IgA levels between the control and exposed groups. Slightly higher 1-OHP levels in smoking users were observed. For the dose-response relationship of IgG, IgA, IgM, and IgE by 1-OHP, each one percentage increase in urinary 1-OHP generates a 0.109%, 0.472%, 0.051%, and 0.067% decrease in control group and generates a 0.312%, 0.538%, 0.062%, and 0.071% decrease in exposed group, respectively. Except for age, alcohol and smoking status, IgM, and IgE, a significant correlation in urinary 1-OHP and other biomarkers in the total population was observed. Additionally, a significant negative correlation in genotoxic/oxidative damage biomarkers of MDA, 8-OH-dG, CTL levels, and immunoglobins of IgG and IgA levels, especially in coke oven workers, was found. These data suggest that oxidative stress/DNA damage induced by PAHs may play a role in toxic responses for PAHs in immunological functions.

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Journal articles on the topic 'Genotoxic stress response'

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