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The regulation of double-strand break repair pathways[edit]

DNA damage response[edit]

DNA damage response (DDR) is the overarching mechanism which mediates the cell's detection and response to DNA damage. This includes the process of detecting DSB within the cell, and the subsequent triggering and regulation of DSB repair pathways. Upstream detections of DNA damage via DDR will lead to the activation of downstream responses such as senescence, cell apoptosis, halting transcription and activating DNA repair mechanisms.[1] Proteins such as the proteins ATM, ATR and DNA-dependent protein kinase (DNA-PK) are vital for the process of detection of DSB in DDR, and these proteins are recruited to the DSB site in the DNA.[2] In particular, ATM has been identified as the protein kinase in charge of the global meditation of cellular responses to DSB, which includes various DSB repair pathways.[2] Following the recruitment of the aforementioned proteins to DNA damage sites, they will in turn trigger cellular responses and repair pathways to mitigate and repair the damage caused.[1] In short, these vital upstream proteins and downstream repair pathways altogether forms the DDR, which plays a vital role in DSB repair pathways regulation.

Fanconi anemia complex in one DNA damage response pathway[edit]

The image in this section illustrates molecular steps in a DNA damage response pathway in which a Fanconi anemia complex is activated during repair of a double-strand break. ATM (ATM) is also a protein kinase that is recruited and activated by DNA double-strand breaks. DNA double-strand damages activate the Fanconi anemia core complex (FANCA/B/C/E/F/G/L/M).[3] The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI.[4] ATM activates (phosphorylates) CHEK2 and FANCD2[5] CHEK2 phosphorylates BRCA1.[6] Ubiquinated FANCD2 complexes with BRCA1 and RAD51.[7] The PALB2 protein acts as a hub,[8] bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.[9] RAD51 plays a major role in homologous recombinational repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a template strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.

Double-strand break repair pathway choice[edit]

As cells have developed various DSB repair models, it is said that specific pathways are favoured for their ability to repair DSB depending on the cellular context.[10] These conditions include the type of DSB involved, the species of cells involved, and the stage of the cell cycle.[11]

In various types of DSB[edit]

Cells have evolved a multitude of DSB repair pathways in response to the various types of DSB.[11] Hence, various pathways are favoured in different situations. For instance, frank DSB, which are DSB induced by substances like as ionizing radiation, and nucleases, can be repaired by both HR and NHEJ. On the other hand, DSB due to replication fork collapse mainly favours HR.[11][12]

In higher eukaryotes and yeast cells[edit]

It is said that the favoured pathway in a particular situations is also largely dependent on the species of the cell, the cell type, and cell cycle phases; and are all modulated and triggered by different upstream regulatory proteins.[11] As compared to higher eukaryotes, yeast cells have adopted HR as the main repair pathway for DSB.[13] Imprecise NHEJ, the primary pathway for NHEJ to repair "dirty" ends due to IR, was found to be inefficent at repairing DSB in yeast cells. It was hypothesized that this inefficiency as compared to mammalian cells is due to the lack of three vital NHEJ proteins, including DNA-PKcs, BRCA1, and Artemis.[11] Contrary to yests, higher eukaryotes has a much higher frequency and efficiency at adopting NHEJ pathways.[14] Research hypothesize that this is due to the higher eukaryote's larger genome size, as it means that more NHEJ related proteins are encoded for NHEJ repair pathways; and a larger genome implies a challenging obstacle to find a homologous template for HR.[11]

In cell cycle[edit]

HR and NHEJ pathways are favoured in various phases of cell cycles for a multitude of factors. As S and G2 phases of the cell cycle generate more chromatids, the increased availability of template access for HR results in the up-regulation of the pathway.[15] This rise is further increased due to the activation of CDK1 and the increase of RAD51 and RAD52 levels during G1 phase.[11][16] Despite this, NHEJ not is inactive during the HR up-regulation. In fact, NHEJ was shown to be active throughout all stages of the cell cycle, and is favoured in G1 phase during low resection action intervals.[17][18] This suggests the competition between HR and NHEJ for DSB repair in cells.[16] It should be noted, however, that there is a shift of favour from NHEJ to HR when the cell cycle is progressing from G1 to S/G2 phases in eukaryotic cells.[16]

During meiosis[edit]

In diploid eukaryotic organisms, the events of meiosis can be viewed as occurring in three steps. (1) Haploid gametes undergo syngamy/fertilisation with the result that chromosome sets of different parental origin come together to share the same nucleus. (2) Homologous chromosomes originating from different cells (i.e. non-sister chromosomes) align in pairs and undergo recombination involving double-strand break repair. (3) Two successive cell divisions (without duplication of chromosomes) result in haploid gametes that can then repeat the meiotic cycle. During step (2), damages in DNA of the germline can be removed by double-strand break repair[19]. In particular, double-strand breaks in one duplex DNA molecule can be accurately repaired using information from a homologous intact DNA molecule by the process of homologous recombination[19].

  1. ^ a b Zhou BB, Elledge SJ (November 2000). "The DNA damage response: putting checkpoints in perspective". Nature. 408 (6811): 433–439. Bibcode:2000Natur.408..433Z. doi:10.1038/35044005. PMID 11100718. S2CID 4419141.
  2. ^ a b Blackford AN, Jackson SP (June 2017). "ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response". Molecular Cell. 66 (6): 801–817. doi:10.1016/j.molcel.2017.05.015. PMID 28622525. S2CID 206997898.
  3. ^ D'Andrea AD (2010). "Susceptibility pathways in Fanconi's anemia and breast cancer". N. Engl. J. Med. 362 (20): 1909–19. doi:10.1056/NEJMra0809889. PMC 3069698. PMID 20484397.
  4. ^ Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME (2009). "The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways". J. Biol. Chem. 284 (38): 25560–8. doi:10.1074/jbc.M109.007690. PMC 2757957. PMID 19633289.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ Castillo P, Bogliolo M, Surralles J (2011). "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair (Amst.). 10 (5): 518–25. doi:10.1016/j.dnarep.2011.02.007. PMID 21466974.
  6. ^ Stolz A, Ertych N, Bastians H (2011). "Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability". Clin. Cancer Res. 17 (3): 401–5. doi:10.1158/1078-0432.CCR-10-1215. PMID 21088254.
  7. ^ Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD (2002). "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood. 100 (7): 2414–20. doi:10.1182/blood-2002-01-0278. PMID 12239151.
  8. ^ Park JY, Zhang F, Andreassen PR (2014). "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". Biochim. Biophys. Acta. 1846 (1): 263–75. doi:10.1016/j.bbcan.2014.06.003. PMC 4183126. PMID 24998779.
  9. ^ Chun J, Buechelmaier ES, Powell SN (2013). "Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway". Mol. Cell. Biol. 33 (2): 387–95. doi:10.1128/MCB.00465-12. PMC 3554112. PMID 23149936.
  10. ^ Chapman JR, Taylor MR, Boulton SJ (August 2012). "Playing the end game: DNA double-strand break repair pathway choice". Molecular Cell. 47 (4): 497–510. doi:10.1016/j.molcel.2012.07.029. PMID 22920291.
  11. ^ a b c d e f g Shrivastav M, De Haro LP, Nickoloff JA (January 2008). "Regulation of DNA double-strand break repair pathway choice". Cell Research. 18 (1): 134–147. doi:10.1038/cr.2007.111. PMID 18157161. S2CID 20992607.
  12. ^ Rothstein R, Michel B, Gangloff S (January 2000). "Replication fork pausing and recombination or "gimme a break"". Genes & Development. 14 (1): 1–10. doi:10.1101/gad.14.1.1. PMID 10640269. S2CID 40751623.
  13. ^ Sugawara N, Haber JE (February 1992). "Characterization of double-strand break-induced recombination: homology requirements and single-stranded DNA formation". Molecular and Cellular Biology. 12 (2): 563–575. doi:10.1128/MCB.12.2.563. PMC 364230. PMID 1732731.
  14. ^ Lin Y, Lukacsovich T, Waldman AS (December 1999). "Multiple pathways for repair of DNA double-strand breaks in mammalian chromosomes". Molecular and Cellular Biology. 19 (12): 8353–8360. doi:10.1128/MCB.19.12.8353. PMC 84924. PMID 10567560.
  15. ^ Dronkert ML, Beverloo HB, Johnson RD, Hoeijmakers JH, Jasin M, Kanaar R (May 2000). "Mouse RAD54 affects DNA double-strand break repair and sister chromatid exchange". Molecular and Cellular Biology. 20 (9): 3147–3156. doi:10.1128/MCB.20.9.3147-3156.2000. PMC 85609. PMID 10757799.
  16. ^ a b c Chen F, Nastasi A, Shen Z, Brenneman M, Crissman H, Chen DJ (September 1997). "Cell cycle-dependent protein expression of mammalian homologs of yeast DNA double-strand break repair genes Rad51 and Rad52". Mutation Research. 384 (3): 205–211. doi:10.1016/S0921-8777(97)00020-7. PMID 9330616.
  17. ^ Aylon Y, Liefshitz B, Kupiec M (December 2004). "The CDK regulates repair of double-strand breaks by homologous recombination during the cell cycle". The EMBO Journal. 23 (24): 4868–4875. doi:10.1038/sj.emboj.7600469. PMC 535085. PMID 15549137.
  18. ^ Ira G, Pellicioli A, Balijja A, Wang X, Fiorani S, Carotenuto W, et al. (October 2004). "DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1". Nature. 431 (7011): 1011–1017. Bibcode:2004Natur.431.1011I. doi:10.1038/nature02964. PMC 4493751. PMID 15496928.
  19. ^ a b Bernstein H, Hopf FA, Michod RE. The molecular basis of the evolution of sex. Adv Genet. 1987;24:323-70. doi: 10.1016/s0065-2660(08)60012-7. PMID: 3324702
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