Checking on DNA damage in S phase

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Abstract
To protect the integrity of their genome, eukaryotic cells possess evolutionarily conserved surveillance mechanisms that are known as checkpoints, which constantly monitor the status and quality of chromosomal DNA and delay cell-cycle progression in response to replication stress or diverse types of DNA damage. The genetically most vulnerable period of the cell cycle, the DNA-synthesis (S) phase, is protected against various genotoxic stresses by three checkpoints. These are the DNA-damage-induced, replication-independent, intra-S-phase checkpoint (the 'intra-S-phase checkpoint'), which is the main topic of this review; the replication-dependent S-phase checkpoint (the 'replication checkpoint'); and the replication-dependent S–M checkpoint (the 'S–M checkpoint'), which prevents mitotic entry when DNA is incompletely replicated. Recent discoveries reveal the distinct molecular mechanisms that activate the two most proximal checkpoint-signalling kinases ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and RAD3 related (ATR), respectively. Furthermore, new evidence sheds light on the identity and function of candidate DNA-damage sensors, such as the NBS1–MRE11–RAD50 (MRN) complex (where NBS1 stands for Nijmegen-breakage-syndrome-1 and MRE11 stands for meiotic-recombination protein-11), as well as other components of the checkpoint-signalling cascades including the effectors. In response to DNA double-strand breaks (DSBs), the activated intra-S-phase checkpoint inhibits DNA replication through the combined action of the ATM/ATR–CHK2/CHK1–CDC25A–CDK2 and the ATM–NBS1–FANCD2/SMC1 effector pathways (where CHK stands for checkpoint kinase; CDK stands for cyclin-dependent kinase; FANCD2 stands for Fanconi anaemia complementation group D2; and SMC1 stands for structural maintenance of chromosomes-1). A recently identified class of proximal checkpoint regulators, termed mediators, include p53-binding protein-1 (53BP1), mediator of DNA-damage checkpoint-1 (MDC1) and breast cancer susceptibility protein-1 (BRCA1) for the ATM-mediated responses, and claspin for ATR. They seem to serve as molecular match-makers that are critical for the timely and coordinated activation and maintenance of the checkpoint responses. Live-cell, real-time imaging of early molecular events that are set in motion after formation of DSBs has provided valuable information about the spatio-temporal orchestration of the DSB response. This includes an unexpectedly dynamic behaviour of the checkpoint proteins that are involved in the recognition, processing, signalling and repair of the DNA lesions. Defects in the genes that encode products that participate in the intra-S-phase checkpoint disable the checkpoint response, and thereby cause unscheduled DNA synthesis in irradiated cells (known as radioresistant DNA synthesis; RDS). Such checkpoint defects cause predisposition to a range of life-threatening human diseases including cancer.