To initiate NHEJ, the Ku70/80 heterodimer (hereafter referred to as Ku) and the DNA-PK catalytic subunit (DNA-PKcs) are recruited to damage sites to generate the DNA-PK holoenzyme ( Gell and Jackson, 1999 Singleton et al., 1999 Jette and Lees-Miller, 2015). Although NHEJ is active in all phases of the cell cycle, it occurs most frequently in G1 phase and repairs about 80% of IR-induced DSBs, making it the predominant repair pathway in mammalian cells ( Burma et al., 2006 Beucher et al., 2009). NHEJ, on the other hand, is fast, selective for two-ended DSBs, and often mutagenic ( Ranjha et al., 2018 Stinson et al., 2020). This process is mostly error-free, can repair protein-blocked ends and is facilitated by RAD51, a recombinase with ATPase activity which initiates strand invasion and DNA synthesis ( Mehta and Haber, 2014). These templates are then used for DNA synthesis and repair of the break ( Symington and Gautier, 2011). To initiate HR, the DNA ends are resected to generate long 3′ single-stranded (ss)DNA overhangs, which pair with homologous sequences.
Homologous recombination is highly accurate and typically occurs in S/G2 phases of the cell cycle when a replicated sister chromatid is present ( Burma et al., 2006 Sullivan and Bernstein, 2018). DSBs are repaired by two major pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ) ( Figure 1).
These kinases signal to downstream cell cycle checkpoints and localize repair machinery to the break ( Blackford and Jackson, 2017). To prevent such outcomes, cells activate a DNA damage response (DDR), which is predominantly mediated by the phosphatidylinositol 3-kinase-related kinase (PIKK) family members, DNA-dependent protein kinase (DNA-PK), ataxia-telangiectasia mutated (ATM), and ATM and RAD3-related (ATR) ( Blackford and Jackson, 2017). However, DSBs caused by DNA damage are almost always detrimental and result in deletions, translocations, and chromosome fusions, which leads to senescence, apoptosis or oncogenesis ( Phillips and McKinnon, 2007 Bohgaki et al., 2010 Bunting and Nussenzweig, 2013 Rulten and Caldecott, 2013 Ghosh et al., 2018 Seol et al., 2018). On the one hand, programmed DSBs can be beneficial to promote genome and antibody diversity in meiosis and V(D)J recombination, respectively. DSBs can be beneficial or detrimental depending on the context. DSB repair and DSB repair choice.ĭNA double strand breaks (DSBs) originate from exposure to both external DNA damaging agents, such as genotoxic chemicals and ionizing radiation (IR), and endogenous sources, such replication fork collapse, reactive oxygen species and chromosome fusions ( Symington and Gautier, 2011 Ceccaldi et al., 2016). In this review, we will focus on these decision points and the mechanisms that dictate end protection vs.
#Decipher backup repair legit series#
The choice of which repair pathway is employed is also dictated by a series of decision points that shift the break toward HR or NHEJ. Additionally, DSBs can be repaired by two major pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ). Accordingly, key decision points are used to shift DNA ends toward DSB repair vs. Yet, the processing of telomeres and DSBs share many commonalities. Decisions to join DNA ends, or not, are therefore critical to genome stability. Telomeres, on the other hand, are specialized, stable DNA ends that must be protected from recognition as DSBs to inhibit unwanted chromosome fusions. DSBs are considered one of the most deleterious forms of DNA damage and must be quickly recognized and repaired. The regulation of DNA double-strand breaks (DSBs) and telomeres are diametrically opposed in the cell.
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