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Homologous DNA Repair:Safeguarding Genome Territories from Knives


Affiliations
1 Department of Microbiology and Molecular Genetics, University of the Punjab, Quaid-e-Azam Campus, Lahore 54590, Pakistan
2 Department of Allied Health Sciences, University of Health Sciences, Lahore 54000, Pakistan
 

DNA damage agents constantly target the genome integrity causing lethal damages. Homologous DNA repair as universal error-free repair pathway constitutively acts to remove double strand breaks. Tumour suppressor genes are the major candidates and mediators of this pathway. In this context, we review the emerging role of BRCA1/PALB2/BRCA2/RAD51 complex and show how BRCA1 interact with different protein partners to be the first-line mediator of homologous DNA repair pathway at the site of DNA damage. A defect anywhere in this BRCA1/PALB2/BRCA2/RAD51 assembly halts formation and stabilization of nuclear foci of BRCA2 at DNA damage sites compromising HDR repair progression.

Keywords

Breast Cancer Susceptibity Gene 1, Hereditary Breast Cancer, Phosphorylation, Replication Protein A, Strand Invasion.
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  • Daley, J. M., Kwon, Y., Niu, H. and Sung, P., Focus: 50 years of DNA repair: the Yale symposium reports: investigations of homologous recombination pathways and their regulation. Yale J. Biol. Med., 2013, 86, 453.

  • Niture, S. K., Khatri, R. and Jaiswal, A. K., Regulation of Nrf2 – an update. Free Rad. Biol. Med., 2014, 66, 36–44.

  • Krejci, L., Altmannova, V., Spirek, M. and Zhao, X., Homologous recombination and its regulation. Nucleic Acids Res., 2012, 40, 5795–5818.

  • Kasparek, T. R. and Humphrey, T. C., DNA double-strand break repair pathways, chromosomal rearrangements and cancer. Semin. Cell Dev. Biol., 2011, 22, 886–897.

  • Thompson, L. H., Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography. Mutat. Res.-Rev. Mutat., 2012, 751, 158–246.

  • Lemaître, C. and Soutoglou, E., Double strand break (DSB) repair in heterochromatin and heterochromatin proteins in DSB repair. DNA Repair., 2014, 19, 163–168.

  • David, R., DNA repair: repair with a twist. Nat. Rev. Mol. Cell Biol., 2013, 14, 268.

  • Chapman, J. R., Taylor, M. R. and Boulton, S. J., Playing the end game: DNA double-strand break repair pathway choice. Mol. Cell., 2012, 47, 497–510.

  • Aparicio, T., Baer, R. and Gautier, J., DNA double-strand break repair pathway choice and cancer. DNA Repair., 2014, 19, 169–175.

  • Wasson, M. K. et al., Association of DNA repair and cell cycle gene variations with breast cancer risk in Northeast Indian population: a multiple interaction analysis. Tumor Biol., 2014, 35(6), 5885–5894.

  • Apostolou, P. and Fostira, F., Hereditary breast cancer: the era of new susceptibility genes. Biomed. Res. Int., 2013.

  • Cybulski, C. et al., Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland. Clin. Genet., 2014.

  • Wang, F., Fang, Q., Ge, Z., Yu, N., Xu, S. and Fan, X., Common BRCA1 and BRCA2 mutations in breast cancer families: a metaanalysis from systematic review. Mol. Biol. Rep., 2012, 39, 2109–2118.

  • Zheng, Y., Zhang, J., Hope, K., Niu, Q., Huo, D. and Olopade, O. I., Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer. Breast Cancer Res. Tr., 2010, 124, 857–861.

  • Park, J. Y., Zhang, F. and Andreassen, P. R., PALB2: the hub of a network of tumor suppressors involved in DNA damage responses. BBA-Rev Cancer, 2014, 1846, 263–275.

  • Suwaki, N., Klare, K. and Tarsounas, M., RAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis. In Semin. Cell Dev. Biol., Academic Press, 2011, pp. 898–905.

  • Zhang, F., Ma, J., Wu, J., Ye, L., Cai, H., Xia, B. and Yu, X., PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol., 2009, 19, 524–529.

  • Yata, K. et al., BRCA2 coordinates the activities of cell-cycle kinases to promote genome stability. Cell, Rep., 2014.

  • Shibata, A. and Jeggo, P., DNA double-strand break repair in a cellular context. Clin. Oncol-UK, 2014, 26, 243–249.

  • Smeenk, G. and Attikum, H. V., The chromatin response to DNA breaks: leaving a mark on genome integrity. Annu. Rev. Biochem., 2013, 82, 55–80.

  • Kass, E. M. and Jasin, M., Collaboration and competition between DNA double-strand break repair pathways. FEBS Lett., 2010, 584, 3703–3708.

  • Symington, L. S. and Gautier, J., Double-strand break end resection and repair pathway choice. Annu. Rev. Genet., 2011, 45, 247–271.

  • Meng, F., Bhupathi, D. and Hart, C. P., DNA repair processes involved with the hypoxia-activated prodrug TH-302: comparison to cisplatin and temozolomide. Cancer Res., 2015, 75, 3867–3867.

  • Metzger, M. J., Stoddard, B. L. and Monnat, Jr R. J., PARPmediated repair, homologous recombination, and back-up non-homologous end joining-like repair of single-strand nicks. DNA Repair, 2013, 12, 529–534.

  • Wang, Q. et al., Rad17 recruits the MRE11‐RAD50‐NBS1 complex to regulate the cellular response to DNA double‐strand breaks. EMBO J., 2014, 33, 862–877.

  • Sakasai, R. et al., CtIP‐and ATR‐dependent FANCJ phosphorylation in response to DNA strand breaks mediated by DNA replication. Genes Cells, 2012, 17, 962–970.

  • Polato, F. et al., CtIP-mediated resection is essential for viability and can operate independently of BRCA1. J. Exp. Med., 2014, 211(6), 1027–1036.

  • Christou, C. M. and Kyriacou, K., BRCA1 and its network of interacting partners. Biology, 2013, 2, 40–63.

  • Cruz-García, A., López-Saavedra, A. and Huertas, P., BRCA1 accelerates CtIP-mediated DNA-end resection. Cell. Rep., 2014, 9(2), 451–459.

  • Escribano-Díaz, C. et al., A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell., 2013, 49, 872–883.

  • Schlacher, K., Wu, H. and Jasin, M., A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell, 2012, 22, 106–116.

  • Buisson, R. and Masson, J. Y., PALB2 self-interaction controls homologous recombination. Nucl. Acids Res., 2012, 40, 10312–10323.

  • Clark, S. L., Rodriguez, A. M., Snyder, R. R., Hankins, G. and Boehning, D., Structure-function of the tumour suppressor BRCA1. Comput. Struct. Biotechnol. J., 2012, 1(1), 1–8.

  • Oliver, A. W., Swift, S., Lord, C. J., Ashworth, A. and Pearl, L. H., Structural basis for recruitment of BRCA2 by PALB2. EMBO. Rep., 2009, 10, 990–996.

  • Nikkilä, J., PALB2 and RAP80 Genes in Hereditary Breast Cancer Predisposition, 2013.

  • Coleman, K. A. and Greenberg, R. A., The BRCA1-RAP80 complex regulates DNA repair mechanism utilization by restricting end resection. J. Biol. Chem., 2011, 286, 13669–13680.

  • Castillo, A. et al., The BRCA1-interacting protein abraxas is required for genomic stability and tumour suppression. Cell. Rep., 2014, 8, 807–817.

  • Venkitaraman, A. R., Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu. Rev. Pathol., 2009, 4, 461–487.

  • Southey, M. C., Teo, Z. L. and Winship, I., PALB2 and breast cancer: ready for clinical translation. Appl. Clin. Genet., 2013, 6, 43.

  • Wark, L. et al., Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three‐dimensional nuclear organization of patient‐derived cell lines. Gene. Chromosome Canc., 2013, 52, 480–494.

  • Sy, S. M. H., Huen, M. S. and Chen, J., MRG15 is a novel PALB2-interacting factor involved in homologous recombination. J. Biol. Chem., 2009, 284, 21127–21131.

  • Shakya, R. et al., BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science, 2011, 334, 525–528.

  • Hayakawa, T., Zhang, F., Hayakawa, N., Ohtani, Y., Shinmyozu, K., Nakayama, J. I. and Andreassen, P. R., MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks. J. Cell Sci., 2010, 123, 1124–1130.

  • Rosen, E. M., BRCA1 in the DNA damage response and at telomeres. Front. Genet., 2013, 4, 85.

  • Joris, P., Amelie, R., Anthony, C., Remi, B. and Jean-Yves, M., Exploring the roles of PALB2 at the crossroads of DNA repair and cancer. Biochem. J., 2014, 460, 331–342.

  • Dray, E. et al., Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2. Nat. Struct. Mol. Biol., 2010, 17, 1255–1259.


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  • Homologous DNA Repair:Safeguarding Genome Territories from Knives

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Authors

Saba Abass
Department of Microbiology and Molecular Genetics, University of the Punjab, Quaid-e-Azam Campus, Lahore 54590, Pakistan
Warda Fatima
Department of Microbiology and Molecular Genetics, University of the Punjab, Quaid-e-Azam Campus, Lahore 54590, Pakistan
Saqib Mahmood
Department of Allied Health Sciences, University of Health Sciences, Lahore 54000, Pakistan

Abstract


DNA damage agents constantly target the genome integrity causing lethal damages. Homologous DNA repair as universal error-free repair pathway constitutively acts to remove double strand breaks. Tumour suppressor genes are the major candidates and mediators of this pathway. In this context, we review the emerging role of BRCA1/PALB2/BRCA2/RAD51 complex and show how BRCA1 interact with different protein partners to be the first-line mediator of homologous DNA repair pathway at the site of DNA damage. A defect anywhere in this BRCA1/PALB2/BRCA2/RAD51 assembly halts formation and stabilization of nuclear foci of BRCA2 at DNA damage sites compromising HDR repair progression.

Keywords


Breast Cancer Susceptibity Gene 1, Hereditary Breast Cancer, Phosphorylation, Replication Protein A, Strand Invasion.

References





DOI: https://doi.org/10.18520/cs%2Fv111%2Fi8%2F1335-1339