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    • Recent studies have demonstrated that in response

    2024-02-05

    Recent studies have demonstrated that in response to IR, hundreds of substrates are phosphorylated in an ATM-dependent manner, clearly demonstrating the complexity of the ATM-mediated DDR pathways (Matsuoka et al., 2007, Bennetzen et al., 2010, Bensimon et al., 2010). However, evidence suggesting that DDR-independent roles of ATM is also emerging. It has been shown that ATM functions in the regulation of signalling pathways involved in maintaining cellular homeostasis, including cellular metabolism, responses to hypoxia and oxidative stress (Ditch & Paull, 2012).
    Ataxia–telangiectasia and Rad3 related activation and downstream signalling Like ATM, ATR is one of the central kinases involved in the DDR. ATR is activated by single stranded DNA structures, which may for example arise at resected DNA DSBs or stalled replication forks. When DNA polymerases stall during DNA replication, the replicative helicases continue to unwind the DNA ahead of the replication fork, leading to the generation of long stretches of single stranded DNA (ssDNA), which are then bound by the single-strand binding protein complex RPA (Replication protein A) (Wold, 1997, Byun et al., 2005). The recruitment of ATR/ATRIP complexes to these sites of replication stress and DNA damage is mediated by direct interaction of ATRIP with ssDNA-bound RPA (Zou & Elledge, 2003). Furthermore, RPA–ssDNA complexes stimulate the binding of the RAD17/RFC2-5 clamp loader complex to the damage sites. The presence of a dsDNA–ssDNA junction activates this complex to load the RAD9–HUS1–RAD1 (9–1–1) heterotrimer onto the DNA ends (Ellison & Stillman, 2001). The 9–1–1 complex in turn recruits TopBP1 which activates ATR (Kumagai et al., 2006, Delacroix et al., 2007, Lee et al., 2007). Once activated, ATR acts via its downstream targets to promote DNA repair, stabilisation and restart of stalled replication forks and transient isoquercitrin arrest (Chen, 2000, Tibbetts et al., 2000, Sørensen et al., 2003, Xiao et al., 2003, Cimprich and Cortez, 2008, Dai and Grant, 2010, Errico and Costanzo, 2012). Many of these functions are mediated through the ATR downstream target CHK1. ATR plays an important role in the enforcement of the Intra-S-phase cell cycle checkpoint during normal S-phase progression and in response to DNA damage. It inhibits the firing of replication origins via mediating the degradation of Cdc25A through CHK1, which in turn slows the progression of DNA replication and provides time for resolution of the stress source (Sørensen et al., 2003, Xiao et al., 2003, Bartek et al., 2004). ATR is also a principal mediator of the G2/M cell cycle checkpoint to prevent the premature entry of cells into mitosis, before DNA replication is completed or in the presence of DNA damage. This ATR dependent G2/M cell cycle arrest is primarily mediated through two mechanisms: (i) the degradation of Cdc25A (Zhao et al., 2002, Xiao et al., 2003) and (ii) the phosphorylation of the Cdc25C phosphatase on serine 216 by CHK1, which creates a binding site for 14-3-3 proteins (Peng et al., 1997, Sanchez et al., 1997). The binding of Cdc25C to 14-3-3 proteins facilitates its export from the nucleus and cytoplasmic sequestration, thereby inhibiting its ability to dephosphorylate and activate nuclear Cdc2, which in turn prevents entry into mitosis (Kumagai and Dunphy, 1999, Graves et al., 2001).
    Interplay between the ataxia–telangiectasia mutated and ataxia–telangiectasia and Rad3 related signalling pathways Although ATM and ATR are activated by different types of DNA damage and act in distinct pathways, their downstream targets and the mediated responses are partially overlapping and dependent on the type of genotoxic stress (Helt et al., 2005). Both kinases share substrate specificity, that is they preferentially phosphorylate serine or threonine residues followed by glutamine (SQ/TQ motif) (Kim et al., 1999, O'Neill et al., 2000, Matsuoka et al., 2007). A large-scale proteomic study analysing proteins phosphorylated on consensus sites recognized by ATM and ATR in response to DNA damage identified over 700 putative targets (Matsuoka et al., 2007). Several of those targets, like p53 and the histone variant H2AX have been shown to be common targets of both kinases (Banin et al., 1998, Canman et al., 1998, Tibbetts et al., 1999, Burma et al., 2001, Ward and Chen, 2001, Friesner et al., 2005). Even CHK1, which is often considered to be the most specific ATR downstream target, can be phosphorylated by ATM in response to IR on both Ser317 and Ser345 (Gatei et al., 2003, Sørensen et al., 2003, Helt et al., 2005). Through these common downstream targets, ATM and ATR cooperate in mediating the cellular responses to many genotoxic stresses and are together responsible for the maintenance of genomic stability by coordinating cell cycle progression with DNA repair (Abraham, 2001, Shiloh, 2003, Cimprich and Cortez, 2008).