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  • ATM is generally regarded to

    2024-06-14

    ATM is generally regarded to be the principal mediator of the G1 Ticarcillin sodium checkpoint, whereas the induction of the intra-S-phase and G2/M checkpoints are usually primarily related to ATR function. However, several studies have demonstrated that, depending on the cellular context and type of DNA damage, ATM also contributes to the activation and maintenance of the intra-S-phase and G2/M cell cycle arrest, suggesting a functional overlap of ATM and ATR signalling in checkpoint activation (Abraham, 2001, Shiloh, 2001). One example is the abovementioned enforcement of the intra-S-phase checkpoint, where both ATM and ATR can target the Cdc25A phosphatase for ubiquitin-dependent degradation thereby regulating the timing of replication origin firing in response to DNA damage (Falck et al., 2001, Xiao et al., 2003, Bartek et al., 2004). This suggests that both ATM and ATR are required for effective activation of the intra-S-phase checkpoint following DNA damage (see Fig. 2). ATM has also been demonstrated to mediate phosphorylation of Cdc25C via CHK2, thereby contributing to the activation of the G2/M cell cycle checkpoint (Matsuoka et al., 1998, Shiloh, 2001, Shiloh, 2003). In agreement with this, Thanasoula et al. have recently demonstrated that both ATM and ATR play a role in preventing telomere dysfunction-driven genomic instability through blocking mitotic entry with uncapped telomeres via degradation of the Cdc25C phosphatase (Thanasoula et al., 2012). Furthermore, studies in Drosophila and fission yeast have implicated that ATM and ATR control partially redundant pathways for telomere maintenance (Bi et al., 2005, Subramanian and Nakamura, 2010). A functional interplay between ATM and ATR in the maintenance of fragile site stability has also been suggested (Ozeri-Galai et al., 2008).
    Ataxia–telangiectasia mutated as a therapeutic target ATM is a known tumour suppressor which is frequently mutated in a broad range of human cancers including lung (Cancer Genome Atlas Research Network, 2012b, Cancer Genome Atlas Research Network, 2014), colorectal (Cancer Genome Atlas Research Network, 2012a), breast (Cancer Genome Atlas Research Network, 2012c) and haematopoietic cancers (Beà et al., 2013, Landau and Wu, 2013). The initial scientific interest in ATM was, however, not focused on its role in tumour development. ATM was first described in 1995 as the gene defective in the autosomal recessive human hereditary disorder ataxia–telangiectasia (A–T) (Savitsky et al., 1995). This disease, caused by a loss of ATM function, is characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, genomic instability, cancer susceptibility and profound sensitivity to ionising radiation (IR) (Taylor et al., 1975, Lavin, 2008). It is primarily this hypersensitivity of ATM-defective cells to IR that has sparked considerable interest in ATM as therapeutic target for cancer therapy (see Table 1). Early studies have demonstrated that caffeine, a methyl xanthine which inhibits the function of both ATM and ATR, sensitises cancer cells to the lethal effects of genotoxic modalities, particularly IR (Blasina et al., 1999, Sarkaria et al., 1999). Interestingly, this sensitising effect was more pronounced in cells defective in p53, indicating that ATM and/or ATR inhibition might be particularly effective for the treatment of p53-deficient tumours (Powell et al., 1995, Yao et al., 1996, Bracey et al., 1997). Despite the value of caffeine as an experimental tool for in vitro studies, it is not a clinically useful radiosensitising agent due to systemic toxicity at the doses required for radiosensitisation and the low serum levels that can be achieved in patients (Newton et al., 1981). Wortmannin, a drug originally described as inhibitor of PI3K family members, has also been described as a potent radiosensitiser (Price & Youmell, 1996), an effect subsequently shown to be mediated through potent inhibition of both ATM and DNA-PKcs (Sarkaria et al., 1998). However, similar to caffeine, a lack of selectivity and high in vivo toxicity has hindered further development of this drug for the clinic (Karve et al., 2012).