ATM in prevention of genomic instability

ATM (ataxia-telangiectasia mutated) kinase is a key factor in DNA damage responses, and mutations in ATM cause AT (ataxia-telangi-ectasia), a form of genomic instability syndrome. 1 Various forms of genotoxic agents that generate DsB (double-stranded DNA breaks) activate ATM and induce DNA damage checkpoint pathways involving cell cycle arrest and repair of legions. ATM plays a central role in maintenance of genomic stability, and recent studies indicate that other environmental signals, including hypoxic conditions and oxidative stress, as well as alteration of chromatin structures, can activate ATM, 2-4 which then transduces various cellular signal-ing pathways that help cells maintain their genetic integrity. 5 Among various errors that could occur during the course of DNA replication, rereplication may be one of the most del-eterious events that need to be avoided to minimize the genomic instability. Thus, cells are equipped with multiple systems that prevent rereplication. 6 This regulation centers on the assembly of pre-RC (pre-replicative complex) that is essential for initiating DNA replication during s phase. Pre-RCs are generated on the chromosomes at the late M to early G 1 and probably all through G 1 phase through recruitment of Mcm (minichromo-some maintenance) onto Orc (origin recognition complex), the core complex of which is constitutively bound to chromatin. This process is facilitated by Cdt1, which binds to Mcm and delivers it onto Orc. 7 Once pre-RC is activated during s phase, and new DNA strands are synthesized, the pre-RC on the replicated DNA templates are inactivated. The expression of Cdt1 is strictly cell cycle-regulated, and the Cdt1 protein is present only during G 1 when pre-RC formation is permitted. Aberrant expression of Cdt1 during s phase can generate pre-RC on the replicated chromosomes , which would be activated to cause rereplication. Rapid degradation of Cdt1 in s phase is ensured by 2 different ubiquitin ligases, namely sCF skp2 dependent on Cdk-mediated phosphorylation and Cul4-DDB1 Cdt2 ubiquitin ligase dependent on PCNA (proliferating cell nuclear antigen). in the February 1, 2013 issue of Cell Cycle, the group led by Masatoshi Fujita reported a novel link between ATM and prevention of rereplication through regulation of Cdt1 stability. 8 in ATM-depleted cells and cells from AT patients, expression of Cdt1 is deregulated during s phase, which renders these cells more prone to rereplicate their genomes. The authors have concluded that the ATM-Akt-sCF skp2 pathway may play a role to ensure the complete degradation of Cdt1 …