Cell cycle control, checkpoint mechanisms, and genotoxic stress.

Abstract

The ability of cells to maintain genomic integrity is vital for cell survival and proliferation. Lack of fidelity in DNA replication and maintenance can result in deleterious mutations leading to cell death or, in multicellular organisms, cancer. The purpose of this review is to discuss the known signal transduction pathways that regulate cell cycle progression and the mechanisms cells employ to insure DNA stability in the face of genotoxic stress. In particular, we focus on mammalian cell cycle checkpoint functions, their role in maintaining DNA stability during the cell cycle following exposure to genotoxic agents, and the gene products that act in checkpoint function signal transduction cascades. Key transitions in the cell cycle are regulated by the activities of various protein kinase complexes composed of cyclin and cyclin-dependent kinase (Cdk) molecules. Surveillance control mechanisms 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 delay that provides the cell more time to repair damage before progressing to the next phase of the cycle. A variety of cellular responses are elicited that function in checkpoint signaling to inhibit cyclin/Cdk activities. These responses include the p53-dependent and p53-independent induction of Cdk inhibitors and the p53-independent inhibitory phosphorylation of Cdk molecules themselves. Eliciting proper Gl, S, and G2 checkpoint responses to double-strand DNA breaks requires the function of the Ataxia telangiectasia mutated gene product. Several human heritable cancer-prone syndromes known to alter DNA stability have been found to have defects in checkpoint surveillance pathways. Exposures to several common sources of genotoxic stress, including oxidative stress, ionizing radiation, UV radiation, and the genotoxic compound benzo[alpyrene, elicit cell cycle checkpoint responses that show both similarities and differences in their molecular signaling. -Environ Health Perspect 107(Suppl 1):5-24 (1999 (Figure 1) (6,8).The description of the cell cycle being divided into four phases led to many questions about the regulatory mechanisms cells employ to ensure an ordered and sequential progression from G1 to M phase, as well as the mechanisms ensuring DNA stability. Some of these questions were summarized as the "completion" and "alternation" problems (8,9). In the completion problem, the question is raised as to how cells ensure that specific events are completed before subsequent events are initiated. For example, cells must ensure that once DNA is condensed for segregation during cytokinesis, it remains condensed throughout M phase and does not prematurely decondense. In the alternation problem, the question is raised as to how cells ensure that once an event is completed, it is not inappropriately repeated. For example, cells must ensure that once DNA replication in S phase is completed, it is followed by DNA co...

P53 and radiation responses

“…As Crick expected, life does not take these challenges without response. Cells have evolved elaborate defense mechanisms to protect against DNA damage (Hartwell and Weinert, 1989;Elledge, 1996;Kaufmann and Paules, 1996;Shackelford et al, 1999). The first insight into this type of process was obtained in bacteria.…”

Identification of genes responsive to BPDE treatment in HeLa cells using cDNA expression assays

“…These stresses include physical (such as heat shock and sheer stress) [Okahara et al, 1995;Polla et al, 1995;Donadelli et al, 1998;Shinoki et al, 1998] and chemical (such as oxidative stresses) [Blackburn et al, 1999;Carper et al, 1999] stimuli that elicit specific genetic responses as well as the expression of some general stress genes [Keyse and Emslie, 1992]. In addition, there are genotoxic stresses [Amundson et al, 1999;Shackelford et al, 1999], which create DNA damage and hence impose a challenge to many cellular and molecular functions. In such cases, cells respond by controlling cell cycle regulation and optimizing DNA repair.…”

Cell Cycle Sensing of Oxidative Stress in Saccharomyces cerevisiae by Oxidation of a Specific Cysteine Residue in the Transcription Factor Swi6p

“…Cell cycle initiation and progression are tightly regulated to ensure that cell division does not take place under unfavorable conditions (4,5). In proliferating cells, oxidative stress can arise from reactive oxygen species that are generated from incomplete reduction of oxygen from the electron transport chain.…”