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    • Of the many different types

    2022-12-02

    Of the many different types of DNA lesions, DNA double strand breaks (DSBs) are amongst the most deleterious. It has been suggested that a single unrepaired DSB may be sufficient to induce cell death (Bennett et al., 1993), whereas misrepaired DSBs can result in loss of genetic information, potentially harmful mutations or chromosomal rearrangements, which can lead to cancer development. ATM is one of the central kinases involved in the cellular response to DNA DSBs which may arise, for example, intrinsically through the collapse of stalled replication forks or extrinsically through exposure to ionising radiation (IR) (van Gent et al., 2001). Despite great advancement in our understanding of ATM signalling and function in recent years, the complex mechanisms involved in its activation are not yet fully resolved. In its inactive state, ATM forms homodimers or higher order multimers which dissociate into active monomers following rapid intermolecular autophosphorylation of serine 1981 upon ATM activation (Bakkenist & Kastan, 2003). Since the initial discovery of this autophosphorylation site and its role in ATM activation, other ATM posttranslational modifications have been reported, including additional SB 258719 hydrochloride synthesis sites and an acetylation site, which regulate ATM activity (Kozlov et al., 2006, Sun et al., 2007). The recruitment of ATM to sites of DNA DSBs is mediated via the MRE11–RAD50–NBS1 (MRN) complex (Lee & Paull, 2005). The MRN complex quickly assembles at sites of DNA DSBs, where it acts as a damage sensor that can also form a physical bridge spanning the DSB (Stracker & Petrini, 2011). ATM recruitment has been shown to require its binding to the C-terminus of NBS1, an interaction that also enhances the kinase activity of ATM (You et al., 2005). Immediately following its recruitment to sites of DNA DSBs, ATM contributes to the phosphorylation of the histone variant H2AX on Serine 139 (referred to as γH2AX) (Burma et al., 2001). H2AX phosphorylation in turn initiates a cascade which assembles DDR components at the breakage site (Paull et al., 2000, Scully and Xie, 2013). Interestingly, MRN complex components not only modulate the activity of ATM, but are also amongst its downstream targets (Lim et al., 2000, Di Virgilio et al., 2009, Gatei et al., 2011, Gatei et al., 2000). This suggests that ATM and the MRN complex work together at the sites of DNA DSBs to fine-tune the recruitment and dissociation of DDR factors and promote effective DNA damage repair. ATM plays a crucial role in the activation of the G1/S cell cycle checkpoint, which prevents cells with damaged DNA from entering S-phase. This response is primarily mediated through the tumour suppressor protein p53, which was one of the first ATM downstream targets to be reported. In response to the induction of SB 258719 hydrochloride synthesis DNA DSBs, ATM directly phosphorylates p53 on serine 15 (Kastan et al., 1992, Siliciano et al., 1997, Banin et al., 1998, Canman et al., 1998). Checkpoint kinase 2 (CHK2) a key downstream target of ATM (Matsuoka et al., 1998) and mediator of ATM signalling also phosphorylates p53, on serine 20 (Chehab et al., 1999, Chehab et al., 2000). This phosphorylation of p53 leads to its stabilisation by preventing its Mdm2-mediated ubiquitinylation and degradation (Haupt et al., 1997, Chehab et al., 1999, Marine and Lozano, 2010). ATM further contributes to the accumulation and stabilisation of p53 by directly phosphorylating Mdm2 (Khosravi et al., 1999). Upon activation and accumulation in the nucleus, p53 acts as transcription factor and drives the expression of genes involved in cell cycle checkpoint activation, such as p21, but also several genes which are involved in the induction of apoptosis (Sullivan et al., 2012). In addition to its role in the G1/S checkpoint, ATM also contributes to the activation of an intra-S-phase checkpoint, as cells deficient in ATM do not reduce DNA synthesis following induction of DNA DSBs, a phenotype referred to as radioresistant DNA synthesis (Houldsworth and Lavin, 1980, Falck et al., 2001). The S-phase checkpoint functions of ATM in response to IR are partly mediated through phosphorylation of NBS1 and SMC1, a component of the cohesion complex (Lim et al., 2000, Kitagawa et al., 2004). Additional enforcement of the intra-S-phase checkpoint by ATM is mediated through its activation of CHK2, which induces ubiquitinylation and degradation of the S-phase-promoting phosphatase Cdc25A (Falck et al., 2001). Cdc25A promotes S-phase progression through activation of the cyclin-dependent kinase 2 (Cdk2) that is needed for DNA synthesis.