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  • DSBs can be repaired by two major pathways

    2020-02-21

    DSBs can be repaired by two major pathways: canonical non-homologous end-joining (c-NHEJ) and homologous recombination (HR) (Chapman et al., 2012). c-NHEJ comprises two sub-pathways, a resection-independent process and a resection-dependent process, and can rejoin break ends with little or no sequence homology (Biehs et al., 2017, Löbrich and Jeggo, 2017). It is the major pathway for repairing two-ended breaks and functions throughout the Teicoplanin (Rothkamm et al., 2003, Panier and Boulton, 2014). HR, in contrast, is restricted to the S and G2 phases of the cell cycle when a sister chromatid is available as a template for repair (van Gent et al., 2001). HR is initiated by long-range resection of the 5′ end and Rad51 loading to single-stranded DNA. Later stages of HR involve homology search, DNA strand invasion to form a displacement loop (D-loop), Rad51 removal, and repair synthesis to copy the missing sequence information at the break site from the donor sister chromatid (Renkawitz et al., 2014). Rad54 has been described to be required for Rad51 removal but also has roles in Rad51 filament stabilization and chromatin remodeling during strand invasion (Sugawara et al., 2003, Sinha and Peterson, 2008, Heyer, 2015, Spies et al., 2016). HR of two-ended DSBs can proceed by two different sub-pathways. One process involves the formation of a double Holliday junction (dHJ) after D-loop formation, which can undergo either dissolution or resolution, in the latter case with the potential for crossover formation between the two sister chromatids (Mehta and Haber, 2014). The other HR sub-pathway is called synthesis-dependent strand annealing (SDSA) and proceeds by displacing the invading strand from the donor sequence after repair synthesis to anneal it with the second, unengaged break end, thereby preventing dHJ formation and crossover products (Heyer, 2015, Haber, 2016). It is currently unclear what regulates whether the D-loop intermediate is processed into a dHJ or displaced to engage in the SDSA sub-pathway. In contrast to two-ended exogenously induced DSBs, which can be repaired by HR and c-NHEJ, one-ended DSBs arising at the replication fork are predominantly repaired by HR (Moynahan and Jasin, 2010). Such DSBs occur endogenously when replication forks encounter spontaneous base damage and/or single-strand breaks but also arise from agents inducing such single-stranded lesions (Ensminger et al., 2014). Additionally, HR factors are important for protecting stalled replication forks and their absence leads to degradation of newly synthesized DNA (Zeman and Cimprich, 2014). In order for DNA repair to take place, chromatin undergoes extensive reorganization and modification, allowing access to DNA and regulating subsequent repair (Smeenk and van Attikum, 2013, Gursoy-Yuzugullu et al., 2016). A key aspect of chromatin modification is the exchange of canonical histones for variants that serve specific functions in physiological conditions and in response to DNA damage. One main histone variant shown to be involved in DNA repair is the histone H3.3. Unlike the canonical histone H3.1, whose expression peaks in S phase, H3.3 is constitutively expressed throughout the cell cycle, and its incorporation is replication independent (Ahmad and Henikoff, 2002). H3.3 is rapidly deposited at sites of UV damage and facilitates recovery of transcription and replication fork progression after repair (Adam et al., 2013, Frey et al., 2014). Additionally, it is exchanged into chromatin at DSBs to promote NHEJ and is involved in post-repair chromatin assembly (Li and Tyler, 2016, Luijsterburg et al., 2016). Two distinct chaperon complexes mediate H3.3 deposition. The histone regulator A (HIRA) directs H3.3 incorporation in promoters of actively transcribed genes and gene bodies, and the chromatin remodeler alpha-thalassemia mental retardation X-linked protein (ATRX) interacts with the death-domain-associated protein (DAXX) to deposit H3.3 in telomeric and pericentric heterochromatin (Drané et al., 2010, Goldberg et al., 2010).