Cell cycle control, checkpoint mechanisms, and genotoxic stress

The ability of cells to maintain genomic integrity is vital for cell surviv al and proliferation. Lack of fidelity in DNA replication and maintenance c an result in deleterious mutations leading to cell death or, in multicellul ar organisms, cancer. The purpose of this review is to discuss the known si gnal transduction pathways that regulate cell cycle progression and the mec hanisms cells employ to insure DNA stability in the lace of genotoxic stres s. In particular, we focus on mammalian cell cycle checkpoint functions, th eir role in maintaining DNA stability during the cell cycle following expos ure to genotoxic agents, and the gene products that act in checkpoint funct ion signal transduction cascades. Key transitions in the cell cycle are reg ulated by the activities of various protein kinase complexes composed oi cy clin and cyclin-dependent kinase (Cdk) molecules. Surveillance control mech anisms that check to ensure proper completion of early events and cellular integrity before initiation of subsequent events in cell cycle progression are referred to as cell cycle checkpoints and can generate a transient dela y that provides the cell more time to repair damage before progressing to t he next phase of the cycle. A variety of cellular responses are elicited th at function in checkpoint signaling to inhibit cyclin/Cdk activities. These responses include the p53-dependent and p53-independent induction of Cdk i nhibitors and the p53-independent inhibitory phosphorylation of Cdk molecul es themselves. Eliciting proper G1, S, and G2 checkpoint responses to doubl e-strand DNA breaks requires the function of the Ataxia telangiectasia muta ted gene product. Several human heritable cancer-prone syndromes known to a lter DNA stability have been found to have defects in checkpoint surveillan ce pathways. Exposures to several common sources of genotoxic stress, inclu ding oxidative stress, ionizing radiation, UV radiation, and the genotoxic compound benzo[a]pyrene, elicit cell cycle checkpoint responses that show b oth similarities and differences in their molecular signaling.