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Journal articles on the topic 'Ligase IV/XRCC4'

Author: Grafiati

Published: 6 September 2023

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1

Nick McElhinny, Stephanie A., Carey M. Snowden, Joseph McCarville, and Dale A. Ramsden. "Ku Recruits the XRCC4-Ligase IV Complex to DNA Ends." Molecular and Cellular Biology 20, no. 9 (2000): 2996–3003. http://dx.doi.org/10.1128/mcb.20.9.2996-3003.2000.

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ABSTRACT Genetic experiments have determined that Ku, XRCC4, and ligase IV are required for repair of double-strand breaks by the end-joining pathway. The last two factors form a tight complex in cells. However, ligase IV is only one of three known mammalian ligases and is intrinsically the least active in intermolecular ligation; thus, the biochemical basis for requiring this ligase has been unclear. We demonstrate here a direct physical interaction between the XRCC4-ligase IV complex and Ku. This interaction is stimulated once Ku binds to DNA ends. Since XRCC4-ligase IV alone has very low DNA binding activity, Ku is required for effective recruitment of this ligase to DNA ends. We further show that this recruitment is critical for efficient end-joining activity in vitro. Preformation of a complex containing Ku and XRCC4-ligase IV increases the initial ligation rate 20-fold, indicating that recruitment of the ligase is an important limiting step in intermolecular ligation. Recruitment by Ku also allows XRCC4-ligase IV to use Ku's high affinity for DNA ends to rapidly locate and ligate ends in an excess of unbroken DNA, a necessity for end joining in cells. These properties are conferred only on ligase IV, because Ku does not similarly interact with the other mammalian ligases. We have therefore defined cell-free conditions that reflect the genetic requirement for ligase IV in cellular end joining and consequently can explain in molecular terms why this factor is required.

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2

Wu, Peï-Yu, Philippe Frit, SriLakshmi Meesala, et al. "Structural and Functional Interaction between the Human DNA Repair Proteins DNA Ligase IV and XRCC4." Molecular and Cellular Biology 29, no. 11 (2009): 3163–72. http://dx.doi.org/10.1128/mcb.01895-08.

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ABSTRACT Nonhomologous end-joining represents the major pathway used by human cells to repair DNA double-strand breaks. It relies on the XRCC4/DNA ligase IV complex to reseal DNA strands. Here we report the high-resolution crystal structure of human XRCC4 bound to the carboxy-terminal tandem BRCT repeat of DNA ligase IV. The structure differs from the homologous Saccharomyces cerevisiae complex and reveals an extensive DNA ligase IV binding interface formed by a helix-loop-helix structure within the inter-BRCT linker region, as well as significant interactions involving the second BRCT domain, which induces a kink in the tail region of XRCC4. We further demonstrate that interaction with the second BRCT domain of DNA ligase IV is necessary for stable binding to XRCC4 in cells, as well as to achieve efficient dominant-negative effects resulting in radiosensitization after ectopic overexpression of DNA ligase IV fragments in human fibroblasts. Together our findings provide unanticipated insight for understanding the physical and functional architecture of the nonhomologous end-joining ligation complex.

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3

Malashetty, Vidyasagar, Audrey Au, Jose Chavez, et al. "The DNA binding domain and the C-terminal region of DNA Ligase IV specify its role in V(D)J recombination." PLOS ONE 18, no. 2 (2023): e0282236. http://dx.doi.org/10.1371/journal.pone.0282236.

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DNA Ligase IV is responsible for the repair of DNA double-strand breaks (DSB), including DSBs that are generated during V(D)J recombination. Like other DNA ligases, Ligase IV contains a catalytic core with three subdomains—the DNA binding (DBD), the nucleotidyltransferase (NTD), and the oligonucleotide/oligosaccharide-fold subdomain (OBD). Ligase IV also has a unique C-terminal region that includes two BRCT domains, a nuclear localization signal sequence and a stretch of amino acid that participate in its interaction with XRCC4. Out of the three mammalian ligases, Ligase IV is the only ligase that participates in and is required for V(D)J recombination. Identification of the minimal domains within DNA Ligase IV that contribute to V(D)J recombination has remained unresolved. The interaction of the Ligase IV DNA binding domain with Artemis, and the interaction of its C-terminal region with XRCC4, suggest that both of these regions that also interact with the Ku70/80 heterodimer are important and might be sufficient for mediating participation of DNA Ligase IV in V(D)J recombination. This hypothesis was investigated by generating chimeric ligase proteins by swapping domains, and testing their ability to rescue V(D)J recombination in Ligase IV-deficient cells. We demonstrate that a fusion protein containing Ligase I NTD and OBDs flanked by DNA Ligase IV DBD and C-terminal region is sufficient to support V(D)J recombination. This chimeric protein, which we named Ligase 37, complemented formation of coding and signal joints. Coding joints generated with Ligase 37 were shorter than those observed with wild type DNA Ligase IV. The shorter length was due to increased nucleotide deletions and decreased nucleotide insertions. Additionally, overexpression of Ligase 37 in a mouse pro-B cell line supported a shift towards shorter coding joints. Our findings demonstrate that the ability of DNA Ligase IV to participate in V(D)J recombination is in large part mediated by its DBD and C-terminal region.

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4

Mahajan, Kiran N., Stephanie A. Nick McElhinny, Beverly S. Mitchell та Dale A. Ramsden. "Association of DNA Polymerase μ (pol μ) with Ku and Ligase IV: Role for pol μ in End-Joining Double-Strand Break Repair". Molecular and Cellular Biology 22, № 14 (2002): 5194–202. http://dx.doi.org/10.1128/mcb.22.14.5194-5202.2002.

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ABSTRACT Mammalian DNA polymerase μ (pol μ) is related to terminal deoxynucleotidyl transferase, but its biological role is not yet clear. We show here that after exposure of cells to ionizing radiation (IR), levels of pol μ protein increase. pol μ also forms discrete nuclear foci after IR, and these foci are largely coincident with IR-induced foci of γH2AX, a previously characterized marker of sites of DNA double-strand breaks. pol μ is thus part of the cellular response to DNA double-strand breaks. pol μ also associates in cell extracts with the nonhomologous end-joining repair factor Ku and requires both Ku and another end-joining factor, XRCC4-ligase IV, to form a stable complex on DNA in vitro. pol μ in turn facilitates both stable recruitment of XRCC4-ligase IV to Ku-bound DNA and ligase IV-dependent end joining. In contrast, the related mammalian DNA polymerase β does not form a complex with Ku and XRCC4-ligase IV and is less effective than pol μ in facilitating joining mediated by these factors. Our data thus support an important role for pol μ in the end-joining pathway for repair of double-strand breaks.

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5

Przewloka, Marcin R., Paige E. Pardington, Steven M. Yannone, David J. Chen, and Robert B. Cary. "In Vitro and In Vivo Interactions of DNA Ligase IV with a Subunit of the Condensin Complex." Molecular Biology of the Cell 14, no. 2 (2003): 685–97. http://dx.doi.org/10.1091/mbc.e01-11-0117.

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Several findings have revealed a likely role for DNA ligase IV, and interacting protein XRCC4, in the final steps of mammalian DNA double-strand break repair. Recent evidence suggests that the human DNA ligase IV protein plays a critical role in the maintenance of genomic stability. To identify protein–protein interactions that may shed further light on the molecular mechanisms of DSB repair and the biological roles of human DNA ligase IV, we have used the yeast two-hybrid system in conjunction with traditional biochemical methods. These efforts have resulted in the identification of a physical association between the DNA ligase IV polypeptide and the human condensin subunit known as hCAP-E. The hCAP-E polypeptide, a member of the Structural Maintenance of Chromosomes (SMC) super-family of proteins, coimmunoprecipitates from cell extracts with DNA ligase IV. Immunofluorescence studies reveal colocalization of DNA ligase IV and hCAP-E in the interphase nucleus, whereas mitotic cells display colocalization of both polypeptides on mitotic chromosomes. Strikingly, the XRCC4 protein is excluded from the area of mitotic chromosomes, suggesting the formation of specialized DNA ligase IV complexes subject to cell cycle regulation. We discuss our findings in light of known and hypothesized roles for ligase IV and the condensin complex.

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6

Francis, Dailia B., Mikhail Kozlov, Jose Chavez, et al. "DNA Ligase IV regulates XRCC4 nuclear localization." DNA Repair 21 (September 2014): 36–42. http://dx.doi.org/10.1016/j.dnarep.2014.05.010.

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7

Roy, Sunetra, Abinadabe J. de Melo, Yao Xu, et al. "XRCC4/XLF Interaction Is Variably Required for DNA Repair and Is Not Required for Ligase IV Stimulation." Molecular and Cellular Biology 35, no. 17 (2015): 3017–28. http://dx.doi.org/10.1128/mcb.01503-14.

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The classic nonhomologous end-joining (c-NHEJ) pathway is largely responsible for repairing double-strand breaks (DSBs) in mammalian cells. XLF stimulates the XRCC4/DNA ligase IV complex by an unknown mechanism. XLF interacts with XRCC4 to form filaments of alternating XRCC4 and XLF dimers that bridge DNA endsin vitro, providing a mechanism by which XLF might stimulate ligation. Here, we characterize two XLF mutants that do not interact with XRCC4 and cannot form filaments or bridge DNAin vitro. One mutant is fully sufficient in stimulating ligation by XRCC4/Lig4in vitro; the other is not. This separation-of-function mutant (which must function as an XLF homodimer) fully complements the c-NHEJ deficits of some XLF-deficient cell strains but not others, suggesting a variable requirement for XRCC4/XLF interaction in living cells. To determine whether the lack of XRCC4/XLF interaction (and potential bridging) can be compensated for by other factors, candidate repair factors were disrupted in XLF- or XRCC4-deficient cells. The loss of either ATM or the newly described XRCC4/XLF-like factor, PAXX, accentuates the requirement for XLF. However, in the case of ATM/XLF loss (but not PAXX/XLF loss), this reflects a greater requirement for XRCC4/XLF interaction.

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8

Recuero-Checa, María A., Andrew S. Doré, Ernesto Arias-Palomo, et al. "Electron microscopy of Xrcc4 and the DNA ligase IV–Xrcc4 DNA repair complex." DNA Repair 8, no. 12 (2009): 1380–89. http://dx.doi.org/10.1016/j.dnarep.2009.09.007.

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9

Hayden, Patrick, Prerna Tewari, Anthony Staines, et al. "Variation in DNA Repair Genes XRCC3, XRCC4, and XRCC5 and Risk of Myeloma." Blood 108, no. 11 (2006): 3416. http://dx.doi.org/10.1182/blood.v108.11.3416.3416.

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Abstract Aberrant class switch recombination (CSR), the physiological process that regulates maturation of the antibody response, is believed to be an early event in the pathogenesis of myeloma. The genetic basis of CSR, from initiation of the DNA double-strand break through to detection and repair, has been elucidated. We hypothesised that germline polymorphisms in the genes implicated in DNA double strand break repair may contribute to susceptibility to myeloma. We therefore assessed 32 SNPs in 3 genes central to the DNA repair pathway in patients with myeloma and controls from the EpiLymph Study, a European study of the epidemiology of lymphoid neoplasms, and from an Irish hospital registry (306 cases, 263 controls). The genes examined were XRCC3, XRCC4, and XRCC5. XRCC3 is a member of the RecA/Rad51-related protein family that participates in homologous recombination. The XRCC4 protein forms a complex with DNA ligase IV and DNA-dependent protein kinase in the repair of DNA double-strand breaks by non-homologous end joining. XRCC5 encodes the 80-kilodalton subunit of the Ku heterodimer protein, the DNA-binding component of the DNA-dependent protein kinase. SNPs from the chosen genes were identified from HapMap CEU Phase I and II genotype data (Public Release #20; 2006-01-24). Haplotype-tagging SNPs (htSNPs) were chosen based on Tagger analysis (as implemented in Haploview Version 3.2). A SNP in GSTP1 was also genotyped to allow for comparison with allele frequencies previously generated from a myeloma cohort. Genotyping was performed using TaqMan®-based assays on the 7900 ABI HT platform. The drop-out rate was consistently less than 3% in all assays. For quality control (QC) purposes, duplicates of 10% of the samples were interspersed throughout the plates. The concordance rates for QC samples were greater than 98%. GSTP1 SNP results were comparable to previously published findings. For the htSNP rs963248 in XRCC4, Allele A was significantly more frequent in cases than in controls (86.4% vs.80.8%) (p=0.0105), as was the AA genotype (74% vs. 65%) (p=0.026). Haplotype analysis was performed using Cocaphase for rs963248 in combination with additional SNPs in XRCC4. The strongest evidence of association came from the A - T haplotype from rs963248-rs2891980 (80.9% vs. 74.5%; p=0.008). For XRCC5, the genotype GG from rs1051685 was detected in 10 cases from different national populations but in only 1 control (p=0.015). Interestingly, this SNP is located in the 3′ UTR of XRCC5. Overall, these data provide support for the hypothesis that common variation in the genes encoding DNA repair proteins contributes to susceptibility to myeloma.

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10

Hsu, Hsin-Ling, Steven M. Yannone, and David J. Chen. "Defining interactions between DNA-PK and ligase IV/XRCC4." DNA Repair 1, no. 3 (2002): 225–35. http://dx.doi.org/10.1016/s1568-7864(01)00018-0.

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11

Wang, Yu, Brandon J. Lamarche, and Ming-Daw Tsai. "Human DNA Ligase IV and the Ligase IV/XRCC4 Complex: Analysis of Nick Ligation Fidelity†." Biochemistry 46, no. 17 (2007): 4962–76. http://dx.doi.org/10.1021/bi0621516.

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12

Liu, Sicheng, Xunyue Liu, Radhika Pankaj Kamdar, et al. "C-terminal region of DNA ligase IV drives XRCC4/DNA ligase IV complex to chromatin." Biochemical and Biophysical Research Communications 439, no. 2 (2013): 173–78. http://dx.doi.org/10.1016/j.bbrc.2013.08.068.

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13

Reid, Dylan A., Sarah Keegan, Alejandra Leo-Macias, et al. "Organization and dynamics of the nonhomologous end-joining machinery during DNA double-strand break repair." Proceedings of the National Academy of Sciences 112, no. 20 (2015): E2575—E2584. http://dx.doi.org/10.1073/pnas.1420115112.

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Nonhomologous end-joining (NHEJ) is a major repair pathway for DNA double-strand breaks (DSBs), involving synapsis and ligation of the broken strands. We describe the use of in vivo and in vitro single-molecule methods to define the organization and interaction of NHEJ repair proteins at DSB ends. Super-resolution fluorescence microscopy allowed the precise visualization of XRCC4, XLF, and DNA ligase IV filaments adjacent to DSBs, which bridge the broken chromosome and direct rejoining. We show, by single-molecule FRET analysis of the Ku/XRCC4/XLF/DNA ligase IV NHEJ ligation complex, that end-to-end synapsis involves a dynamic positioning of the two ends relative to one another. Our observations form the basis of a new model for NHEJ that describes the mechanism whereby filament-forming proteins bridge DNA DSBs in vivo. In this scheme, the filaments at either end of the DSB interact dynamically to achieve optimal configuration and end-to-end positioning and ligation.

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14

Gu, Jiafeng, Haihui Lu, Brigette Tippin, Noriko Shimazaki, Myron F. Goodman, and Michael R. Lieber. "XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps." EMBO Journal 26, no. 4 (2007): 1010–23. http://dx.doi.org/10.1038/sj.emboj.7601559.

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15

Gu, Jiafeng, Haihui Lu, Brigette Tippin, Noriko Shimazaki, Myron F. Goodman, and Michael R. Lieber. "XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps." EMBO Journal 26, no. 14 (2007): 3506–7. http://dx.doi.org/10.1038/sj.emboj.7601729.

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16

Hammel, Michal, Yaping Yu, Shujuan Fang, Susan P. Lees-Miller, and John A. Tainer. "XLF Regulates Filament Architecture of the XRCC4·Ligase IV Complex." Structure 18, no. 11 (2010): 1431–42. http://dx.doi.org/10.1016/j.str.2010.09.009.

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17

Mahaney, Brandi L., Michal Hammel, Katheryn Meek, John A. Tainer, and Susan P. Lees-Miller. "XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair." Biochemistry and Cell Biology 91, no. 1 (2013): 31–41. http://dx.doi.org/10.1139/bcb-2012-0058.

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DNA double strand breaks (DSBs), induced by ionizing radiation (IR) and endogenous stress including replication failure, are the most cytotoxic form of DNA damage. In human cells, most IR-induced DSBs are repaired by the nonhomologous end joining (NHEJ) pathway. One of the most critical steps in NHEJ is ligation of DNA ends by DNA ligase IV (LIG4), which interacts with, and is stabilized by, the scaffolding protein X-ray cross-complementing gene 4 (XRCC4). XRCC4 also interacts with XRCC4-like factor (XLF, also called Cernunnos); yet, XLF has been one of the least mechanistically understood proteins and precisely how XLF functions in NHEJ has been enigmatic. Here, we examine current combined structural and mutational findings that uncover integrated functions of XRCC4 and XLF and reveal their interactions to form long, helical protein filaments suitable to protect and align DSB ends. XLF–XRCC4 provides a global structural scaffold for ligating DSBs without requiring long DNA ends, thus ensuring accurate and efficient ligation and repair. The assembly of these XRCC4–XLF filaments, providing both DNA end protection and alignment, may commit cells to NHEJ with general biological implications for NHEJ and DSB repair processes and their links to cancer predispositions and interventions.

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18

Riballo, Enriqueta, Lisa Woodbine, Thomas Stiff, Sarah A. Walker, Aaron A. Goodarzi, and Penny A. Jeggo. "XLF-Cernunnos promotes DNA ligase IV–XRCC4 re-adenylation following ligation." Nucleic Acids Research 37, no. 2 (2008): 482–92. http://dx.doi.org/10.1093/nar/gkn957.

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19

Jiao, Keping, Juan Qin, Yumei Zhao, and Honglian Zhang. "Genetic effects of XRCC4 and ligase IV genes on human glioma." NeuroReport 27, no. 14 (2016): 1024–30. http://dx.doi.org/10.1097/wnr.0000000000000649.

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20

Stiff, Thomas, Emma Shtivelman, Penny Jeggo, and Boris Kysela. "AHNAK interacts with the DNA ligase IV–XRCC4 complex and stimulates DNA ligase IV-mediated double-stranded ligation." DNA Repair 3, no. 3 (2004): 245–56. http://dx.doi.org/10.1016/j.dnarep.2003.11.001.

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21

Asa, Anie Day D. C., Rujira Wanotayan, Mukesh Kumar Sharma, Kaima Tsukada, Mikio Shimada, and Yoshihisa Matsumoto. "Functional analysis of XRCC4 mutations in reported microcephaly and growth defect patients in terms of radiosensitivity." Journal of Radiation Research 62, no. 3 (2021): 380–89. http://dx.doi.org/10.1093/jrr/rrab016.

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Abstract Non-homologous end joining is one of the main pathways for DNA double-strand break (DSB) repair and is also implicated in V(D)J recombination in immune system. Therefore, mutations in non-homologous end-joining (NHEJ) proteins were found to be associated with immunodeficiency in human as well as in model animals. Several human patients with mutations in XRCC4 were reported to exhibit microcephaly and growth defects, but unexpectedly showed normal immune function. Here, to evaluate the functionality of these disease-associated mutations of XRCC4 in terms of radiosensitivity, we generated stable transfectants expressing these mutants in XRCC4-deficient murine M10 cells and measured their radiosensitivity by colony formation assay. V83_S105del, R225X and D254Mfs*68 were expressed at a similar level to wild-type XRCC4, while W43R, R161Q and R275X were expressed at even higher level than wild-type XRCC4. The expression levels of DNA ligase IV in the transfectants with these mutants were comparable to that in the wild-type XRCC4 transfectant. The V83S_S105del transfectant and, to a lesser extent, D254Mfs*68 transfectant, showed substantially increased radiosensitivity compared to the wild-type XRCC4 transfectant. The W43R, R161Q, R225X and R275X transfectants showed a slight but statistically significant increase in radiosensitivity compared to the wild-type XRCC4 transfectant. When expressed as fusion proteins with Green fluorescent protein (GFP), R225X, R275X and D254Mfs*68 localized to the cytoplasm, whereas other mutants localized to the nucleus. These results collectively indicated that the defects of XRCC4 in patients might be mainly due to insufficiency in protein quantity and impaired functionality, underscoring the importance of XRCC4’s DSB repair function in normal development.

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22

Berg, Elke, Morten O. Christensen, Ilaria Dalla Rosa, et al. "XRCC4 controls nuclear import and distribution of Ligase IV and exchanges faster at damaged DNA in complex with Ligase IV." DNA Repair 10, no. 12 (2011): 1232–42. http://dx.doi.org/10.1016/j.dnarep.2011.09.012.

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23

Kusumoto, Rika, Lala Dawut, Caterina Marchetti, et al. "Werner Protein Cooperates with the XRCC4-DNA Ligase IV Complex in End-Processing†." Biochemistry 47, no. 28 (2008): 7548–56. http://dx.doi.org/10.1021/bi702325t.

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24

Critchlow, Susan E., Richard P. Bowater, and Stephen P. Jackson. "Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV." Current Biology 7, no. 8 (1997): 588–98. http://dx.doi.org/10.1016/s0960-9822(06)00258-2.

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25

Fukuchi, Mikoto, Rujira Wanotayan, Sicheng Liu, Shoji Imamichi, Mukesh Kumar Sharma, and Yoshihisa Matsumoto. "Lysine 271 but not lysine 210 of XRCC4 is required for the nuclear localization of XRCC4 and DNA ligase IV." Biochemical and Biophysical Research Communications 461, no. 4 (2015): 687–94. http://dx.doi.org/10.1016/j.bbrc.2015.04.093.

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26

Ochi, Takashi, Bancinyane Lynn Sibanda, Qian Wu, Dimitri Y. Chirgadze, Victor M. Bolanos-Garcia, and Tom L. Blundell. "Structural Biology of DNA Repair: Spatial Organisation of the Multicomponent Complexes of Nonhomologous End Joining." Journal of Nucleic Acids 2010 (2010): 1–19. http://dx.doi.org/10.4061/2010/621695.

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Nonhomologous end joining (NHEJ) plays a major role in double-strand break DNA repair, which involves a series of steps mediated by multiprotein complexes. A ring-shaped Ku70/Ku80 heterodimer forms first at broken DNA ends, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) binds to mediate synapsis and nucleases process DNA overhangs. DNA ligase IV (LigIV) is recruited as a complex with XRCC4 for ligation, with XLF/Cernunnos, playing a role in enhancing activity of LigIV. We describe how a combination of methods—X-ray crystallography, electron microscopy and small angle X-ray scattering—can give insights into the transient multicomponent complexes that mediate NHEJ. We first consider the organisation of DNA-PKcs/Ku70/Ku80/DNA complex (DNA-PK) and then discuss emerging evidence concerning LigIV/XRCC4/XLF/DNA and higher-order complexes. We conclude by discussing roles of multiprotein systems in maintaining high signal-to-noise and the value of structural studies in developing new therapies in oncology and elsewhere.

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27

Malivert, Laurent, Isabelle Callebaut, Paola Rivera-Munoz, et al. "The C-Terminal Domain of Cernunnos/XLF Is Dispensable for DNA Repair In Vivo." Molecular and Cellular Biology 29, no. 5 (2008): 1116–22. http://dx.doi.org/10.1128/mcb.01521-08.

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ABSTRACT The core nonhomologous end-joining DNA repair pathway is composed of seven factors: Ku70, Ku80, DNA-PKcs, Artemis, XRCC4 (X4), DNA ligase IV (L4), and Cernunnos/XLF (Cernunnos). Although Cernunnos and X4 are structurally related and participate in the same complex together with L4, they have distinct functions during DNA repair. L4 relies on X4 but not on Cernunnos for its stability, and L4 is required for optimal interaction of Cernunnos with X4. We demonstrate here, using in vitro-generated Cernunnos mutants and a series of functional assays in vivo, that the C-terminal region of Cernunnos is dispensable for its activity during DNA repair.

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28

Grawunder, Ulf, Matthias Wilm, Xiantuo Wu, et al. "Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells." Nature 388, no. 6641 (1997): 492–95. http://dx.doi.org/10.1038/41358.

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29

Bryans, Margaret, Mary Carmen Valenzano, and Thomas D. Stamato. "Absence of DNA ligase IV protein in XR-1 cells: evidence for stabilization by XRCC4." Mutation Research/DNA Repair 433, no. 1 (1999): 53–58. http://dx.doi.org/10.1016/s0921-8777(98)00063-9.

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30

Ahnesorg, Peter, Philippa Smith, and Stephen P. Jackson. "XLF Interacts with the XRCC4-DNA Ligase IV Complex to Promote DNA Nonhomologous End-Joining." Cell 124, no. 2 (2006): 301–13. http://dx.doi.org/10.1016/j.cell.2005.12.031.

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31

Sallmyr, Annahita, та Feyruz V. Rassool. "Up-Regulated WRN and DNA Ligase IIIα Are Involved in Alternative NHEJ Repair Pathway of DNA Double Strand Breaks (DSB) in Chronic Myeloid Leukemia (CML)." Blood 110, № 11 (2007): 1016. http://dx.doi.org/10.1182/blood.v110.11.1016.1016.

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Abstract The oncogenic BCR-ABL in CML produces increased reactive oxygen species (ROS) leading to DSB and aberrant repair. We have previously shown that CML cells demonstrate an increased frequency of errors of non homologous end-joining (NHEJ). DSB are repaired by two major pathways, homologous recombination (HR) and NHEJ, the dominant pathway in eukaryotic cells, also known as DNA-PK dependent NHEJ (D-NHEJ). Recent reports have identified alternative or “back-up” NHEJ pathways (B-NHEJ) that are highly error-prone, and may explain the altered DSB repair reported in CML. To determine the mechanism for the aberrant NHEJ repair in CML, we examined steady state levels of D-NHEJ proteins, including Ku70/86, DNA-PKcs, Artemis and DNA Ligase IV/XRCC4 in four different BCR-ABL positive CML cell lines compared with three lymphoblastoid cell lines established from normal individuals and one BCR-ABL negative CML cell line. We find that two key components of D-NHEJ, Artemis (4–7 fold) and DNA Ligase IV (2–3 fold) are down-regulated, compared with controls. These data suggest that D-NHEJ repair is compromised in CML. To determine whether alternative NHEJ repair plays a role in the aberrant repair of DSB in CML cells, we next examined expression levels of DNA Ligase IIIα/XRCC1, PARP and other proteins known to be associated with NHEJ repair, such as the protein found to be deleted in Werner’s syndrome, WRN. We find that WRN and DNA Ligase IIIα are increased (3–6 fold) in BCR-ABL-positive CML compared with control cell lines. Importantly, DNA Ligase IIIα/XRCC1 forms a complex with WRN, suggesting that it may be a new member of the alternative repair pathway. To confirm that up-regulation of DNA Ligase IIIα and WRN are elicited by BCR-ABL, we examined the levels of these proteins in primary samples (N=4) from patients with different levels of BCR-ABL, following treatment with the tyrosine kinase inhibitor Gleevec. WRN and DNA Ligase IIIα are down regulated in patient samples where BCR-ABL levels are significantly decreased. Furthermore, we confirmed that these up-regulated proteins are involved in DSB repair in CML cells because they co-localize to induced DSB in BCR-ABL-positive cell lines stably transfected with DSB-containing DRneo plasmid, using fluorescence in situ hybridization (FISH) co-immunostaining. Importantly we show that siRNA down-regulation of WRN and DNA Ligase IIIα leads to elevated levels of unrepaired DSB and a decreased frequency of DSB repair efficiency in CML cells. In addition siRNA down-regulation of WRN leads to large deletions at the site of repair, while siRNA down-regulation of DNA Ligase IIIα results in an increased frequency of misrepair. Finally, we determined whether “correction” of main NHEJ pathway proteins in CML can lead to a decrease in the frequency of errors of end-joining repair. Over-expression of Artemis using pcDNA constructs in CML cells leads to more correct end-joining, compared with vector transfected controls. We conclude that down-regulation of Artemis and DNA Ligase IV leads to compensatory up-regulation of alternative repair pathways in BCR-ABL-positive CML cells, and suggest a role for a new protein complex in CML, in protecting and joining DNA ends, thus ensuring the survival of CML cells. Inhibition of alternative NHEJ repair may be explored in combination with other agents as a therapeutic strategy in CML.

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Liang, Zhuoyi, Vipul Kumar, Marie Le Bouteiller, et al. "Ku70 suppresses alternative end joining in G1-arrested progenitor B cells." Proceedings of the National Academy of Sciences 118, no. 21 (2021): e2103630118. http://dx.doi.org/10.1073/pnas.2103630118.

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Classical nonhomologous end joining (C-NHEJ) repairs DNA double-strand breaks (DSBs) throughout interphase but predominates in G1 phase when homologous recombination is unavailable. Complexes containing the Ku70/80 (“Ku”) and XRCC4/ligase IV (Lig4) core C-NHEJ factors are required, respectively, for sensing and joining DSBs. While XRCC4/Lig4 are absolutely required for joining RAG1/2 endonuclease (“RAG”)-initiated DSBs during V(D)J recombination in G1-phase progenitor lymphocytes, cycling cells deficient for XRCC4/Lig4 also can join chromosomal DSBs by alternative end-joining (A-EJ) pathways. Restriction of V(D)J recombination by XRCC4/Lig4-mediated joining has been attributed to RAG shepherding V(D)J DSBs exclusively into the C-NHEJ pathway. Here, we report that A-EJ of DSB ends generated by RAG1/2, Cas9:gRNA, and Zinc finger endonucleases in Lig4-deficient G1-arrested progenitor B cell lines is suppressed by Ku. Thus, while diverse DSBs remain largely as free broken ends in Lig4-deficient G1-arrested progenitor B cells, deletion of Ku70 increases DSB rejoining and translocation levels to those observed in Ku70-deficient counterparts. Correspondingly, while RAG-initiated V(D)J DSB joining is abrogated in Lig4-deficient G1-arrested progenitor B cell lines, joining of RAG-generated DSBs in Ku70-deficient and Ku70/Lig4 double-deficient lines occurs through a translocation-like A-EJ mechanism. Thus, in G1-arrested, Lig4-deficient progenitor B cells are functionally end-joining suppressed due to Ku-dependent blockage of A-EJ, potentially in association with G1-phase down-regulation of Lig1. Finally, we suggest that differential impacts of Ku deficiency versus Lig4 deficiency on V(D)J recombination, neuronal apoptosis, and embryonic development results from Ku-mediated inhibition of A-EJ in the G1 cell cycle phase in Lig4-deficient developing lymphocyte and neuronal cells.

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Mahaney, Brandi L., Katheryn Meek, and Susan P. Lees-Miller. "Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining." Biochemical Journal 417, no. 3 (2009): 639–50. http://dx.doi.org/10.1042/bj20080413.

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DNA DSBs (double-strand breaks) are considered the most cytotoxic type of DNA lesion. They can be introduced by external sources such as IR (ionizing radiation), by chemotherapeutic drugs such as topoisomerase poisons and by normal biological processes such as V(D)J recombination. If left unrepaired, DSBs can cause cell death. If misrepaired, DSBs may lead to chromosomal translocations and genomic instability. One of the major pathways for the repair of IR-induced DSBs in mammalian cells is NHEJ (non-homologous end-joining). The main proteins required for NHEJ in mammalian cells are the Ku heterodimer (Ku70/80 heterodimer), DNA-PKcs [the catalytic subunit of DNA-PK (DNA-dependent protein kinase)], Artemis, XRCC4 (X-ray-complementing Chinese hamster gene 4), DNA ligase IV and XLF (XRCC4-like factor; also called Cernunnos). Additional proteins, including DNA polymerases μ and λ, PNK (polynucleotide kinase) and WRN (Werner's Syndrome helicase), may also play a role. In the present review, we will discuss our current understanding of the mechanism of NHEJ in mammalian cells and discuss the roles of DNA-PKcs and DNA-PK-mediated phosphorylation in NHEJ.

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Lu, Haihui, Ulrich Pannicke, Klaus Schwarz, and Michael R. Lieber. "Length-dependent Binding of Human XLF to DNA and Stimulation of XRCC4·DNA Ligase IV Activity." Journal of Biological Chemistry 282, no. 15 (2007): 11155–62. http://dx.doi.org/10.1074/jbc.m609904200.

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Budman, Joe, Sunny A. Kim, and Gilbert Chu. "Processing of DNA for Nonhomologous End-joining Is Controlled by Kinase Activity and XRCC4/Ligase IV." Journal of Biological Chemistry 282, no. 16 (2007): 11950–59. http://dx.doi.org/10.1074/jbc.m610058200.

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Doré, Andrew S., Nicholas Furnham, Owen R. Davies, et al. "Structure of an Xrcc4–DNA ligase IV yeast ortholog complex reveals a novel BRCT interaction mode." DNA Repair 5, no. 3 (2006): 362–68. http://dx.doi.org/10.1016/j.dnarep.2005.11.004.

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Gerodimos, Christina A., Howard H. Y. Chang, Go Watanabe, and Michael R. Lieber. "Effects of DNA end configuration on XRCC4-DNA ligase IV and its stimulation of Artemis activity." Journal of Biological Chemistry 292, no. 34 (2017): 13914–24. http://dx.doi.org/10.1074/jbc.m117.798850.

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Koch, Christine Anne, Roger Agyei, Sarah Galicia, et al. "Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IV." EMBO Journal 23, no. 19 (2004): 3874–85. http://dx.doi.org/10.1038/sj.emboj.7600375.

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Chen, Ling, Kelly Trujillo, Patrick Sung, and Alan E. Tomkinson. "Interactions of the DNA Ligase IV-XRCC4 Complex with DNA Ends and the DNA-dependent Protein Kinase." Journal of Biological Chemistry 275, no. 34 (2000): 26196–205. http://dx.doi.org/10.1074/jbc.m000491200.

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Aceytuno, D., C. G. Piett, Z. Havali-Shahriari, et al. "Clinical dysregulation of DNA repair by the polynucleotide kinase/phosphatase-XRCC4-DNA ligase IV in neurological disease." Annals of Oncology 28 (September 2017): v17. http://dx.doi.org/10.1093/annonc/mdx361.058.

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41

Muylaert, Isabella, and Per Elias. "Knockdown of DNA Ligase IV/XRCC4 by RNA Interference Inhibits Herpes Simplex Virus Type I DNA Replication." Journal of Biological Chemistry 282, no. 15 (2007): 10865–72. http://dx.doi.org/10.1074/jbc.m611834200.

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42

Grawunder, Ulf, David Zimmer, and Michael R. Lieber. "DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains." Current Biology 8, no. 15 (1998): 873–79. http://dx.doi.org/10.1016/s0960-9822(07)00349-1.

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Jayaram, Sumithra, Timra Gilson, Elana S. Ehrlich, Xiao-Fang Yu, Gary Ketner, and Les Hanakahi. "E1B 55k-independent dissociation of the DNA ligase IV/XRCC4 complex by E4 34k during adenovirus infection." Virology 382, no. 2 (2008): 163–70. http://dx.doi.org/10.1016/j.virol.2008.08.045.

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Simsek, Deniz, and Maria Jasin. "Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4–ligase IV during chromosomal translocation formation." Nature Structural & Molecular Biology 17, no. 4 (2010): 410–16. http://dx.doi.org/10.1038/nsmb.1773.

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McFadden, Meghan J., Wilson K. Y. Lee, John D. Brennan, and Murray S. Junop. "Delineation of key XRCC4/Ligase IV interfaces for targeted disruption of non-homologous end joining DNA repair." Proteins: Structure, Function, and Bioinformatics 82, no. 2 (2013): 187–94. http://dx.doi.org/10.1002/prot.24349.

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Jayaram, Sumithra, Gary Ketner, Noritaka Adachi, and Les A. Hanakahi. "Loss of DNA ligase IV prevents recognition of DNA by double-strand break repair proteins XRCC4 and XLF." Nucleic Acids Research 36, no. 18 (2008): 5773–86. http://dx.doi.org/10.1093/nar/gkn552.

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Costantini, Silvia, Lisa Woodbine, Lucia Andreoli, Penny A. Jeggo, and Alessandro Vindigni. "Interaction of the Ku heterodimer with the DNA ligase IV/Xrcc4 complex and its regulation by DNA-PK." DNA Repair 6, no. 6 (2007): 712–22. http://dx.doi.org/10.1016/j.dnarep.2006.12.007.

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Chiruvella, Kishore K., Brian M. Renard, Shanda R. Birkeland, Sham Sunder, Zhuobin Liang, and Thomas E. Wilson. "Yeast DNA ligase IV mutations reveal a nonhomologous end joining function of BRCT1 distinct from XRCC4/Lif1 binding." DNA Repair 24 (December 2014): 37–45. http://dx.doi.org/10.1016/j.dnarep.2014.10.003.

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Modesti, Mauro, Murray S. Junop, Rodolfo Ghirlando, et al. "Tetramerization and DNA Ligase IV Interaction of the DNA Double-strand Break Repair Protein XRCC4 are Mutually Exclusive." Journal of Molecular Biology 334, no. 2 (2003): 215–28. http://dx.doi.org/10.1016/j.jmb.2003.09.031.

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Yoder, Kristine E., and Frederic D. Bushman. "Repair of Gaps in Retroviral DNA Integration Intermediates." Journal of Virology 74, no. 23 (2000): 11191–200. http://dx.doi.org/10.1128/jvi.74.23.11191-11200.2000.

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ABSTRACT Diverse mobile DNA elements are believed to pirate host cell enzymes to complete DNA transfer. Prominent examples are provided by retroviral cDNA integration and transposon insertion. These reactions initially involve the attachment of each element 3′ DNA end to staggered sites in the host DNA by element-encoded integrase or transposase enzymes. Unfolding of such intermediates yields DNA gaps at each junction. It has been widely assumed that host DNA repair enzymes complete attachment of the remaining DNA ends, but the enzymes involved have not been identified for any system. We have synthesized DNA substrates containing the expected gap and 5′ two-base flap structure present in retroviral integration intermediates and tested candidate enzymes for the ability to support repair in vitro. We find three required activities, two of which can be satisfied by multiple enzymes. These are a polymerase (polymerase beta, polymerase delta and its cofactor PCNA, or reverse transcriptase), a nuclease (flap endonuclease), and a ligase (ligase I, III, or IV and its cofactor XRCC4). A proposed pathway involving retroviral integrase and reverse transcriptase did not carry out repair under the conditions tested. In addition, prebinding of integrase protein to gapped DNA inhibited repair reactions, indicating that gap repair in vivo may require active disassembly of the integrase complex.

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