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.
These responses include the pdependent and pindependent induction of Cdk inhibitors and the pindependent inhibitory phosphorylation of Cdk molecules themselves.
Eliciting proper G1, 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[a]pyrene, elicit cell cycle checkpoint responses that show both similarities and differences in their molecular signaling.
National Center for Biotechnology Information , U.
Cell cycle checkpoints review pdf writer
Journal List Environ Health Perspect v. Environ Health Perspect. Author information Copyright and License information Disclaimer. Copyright notice. This article has been cited by other articles in PMC. Abstract The ability of cells to maintain genomic integrity is vital for cell survival and proliferation.
Images in this article Figure 3 on p.
Synthesis of nucleoprotein in bean root cells. Animal cell cycle. Annu Rev Biochem. Growth in size and cell DNA replication. Exp Cell Res. Viewpoint: putting the cell cycle in order. Mammalian cell fusion: studies on the regulation of DNA synthesis and mitosis.
Mammalian cell fusion: induction of premature chromosome condensation in interphase nuclei. Checkpoints: controls that ensure the order of cell cycle events. Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. Principles of CDK regulation.
Cell cycle regulation in irradiated and nonirradiated cells. Semin Oncol. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle.
Cell cycle control, checkpoint mechanisms, and genotoxic stress.
G1 events and regulation of cell proliferation. The role of RB in cell cycle control. Prog Cell Cycle Res. The p53 tumour suppressor gene.
D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol. Independent regulation of human D-type cyclin gene expression during G1 phase in primary human T lymphocytes.
J Biol Chem. Growth-regulated expression of D-type cyclin genes in human diploid fibroblasts.
Suppression of growth factor-induced CYL1 cyclin gene expression by antiproliferative agents. Novel mammalian cyclins CYL genes expressed during G1. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. A novel cyclin encoded by a bcl1-linked candidate oncogene.
D11S, a putative oncogene on chromosome 11q13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL G1 phase progression: cycling on cue. Cloning of a D-type cyclin from murine erythroleukemia cells. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development.
Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Identification of G1 kinase activity for cdk6, a novel cyclin D partner.
Differential expression and regulation of Cyclin D1 protein in normal and tumor human cells: association with Cdk4 is required for Cyclin D1 function in G1 progression. Cyclins and cancer. Cancer Res. DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1.
J Cell Biol.
Cell Cycle Regulation by Checkpoints
The retinoblastoma protein: a master regulator of cell cycle, differentiation and apoptosis. Eur J Biochem. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Human DNA polymerase alpha gene: sequences controlling expression in cycling and serum-stimulated cells.
Easy Biology Class
The role of cellular transcription factor E2F in the regulation of cdc2 mRNA expression and cell cycle control of human hematopoietic cells. Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression.
Regulation of cyclin D1, DNA topoisomerase I, and proliferating cell nuclear antigen promoters during the cell cycle. Gene Expr. Regulation of the cyclin E gene by transcription factor E2F1.
Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. In vivo structure of the human cdc2 promoter: release of a pE2F-4 complex from sequences immediately upstream of the transcription initiation site coincides with induction of cdc2 expression.
Cell cycle regulation of the murine cyclin E gene depends on an E2F binding site in the promoter. Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. The E2F transcription factor activates a replication-dependent human H2A gene in early S phase of the cell cycle. Transcriptional regulation of the dihydrofolate reductase gene. The regulation of E2F by pRB-family proteins. Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family.
Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle.
Isolation of three novel human cyclins by rescue of G1 cyclin Cln function in yeast. Association of human cyclin E with a periodic G1-S phase protein kinase. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition.
Regulation of the cell cycle by the cdk2 protein kinase in cultured human fibroblasts. The cdk2 kinase is required for the G1-to-S transition in mammalian cells.
Cell Cycle Checkpoints (FL-Cancer/02)
The role of cyclin E in cell proliferation, development and cancer. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes.
Cyclin A-associated kinase activity is rate limiting for entrance into S phase and is negatively regulated in G1 by p27Kip1. The A- and B-type cyclin associated cdc2 kinases in Xenopus turn on and off at different times in the cell cycle.
EMBO J. Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B. Cyclin A is required for the onset of DNA replication in mammalian fibroblasts.
The roles of Drosophila cyclins A and B in mitotic control. Role for cyclin A in the dependence of mitosis on completion of DNA replication. Human cyclin-dependent kinase 2 is activated during the S and G2 phases of the cell cycle and associates with cyclin A.
Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in higher eukaryotes. Cyclin A is required at two points in the human cell cycle. A- and B-type cyclins differentially modulate substrate specificity of cyclin-cdk complexes. The retinoblastoma protein is essential for cyclin A repression in quiescent cells. Cell cycle regulation of the human cdc2 gene.
Overexpression of cyclin A but not Skp 2 correlates with the tumor relapse of human hepatocellular carcinoma.
Cell cycle control genes in fission yeast and mammalian cells. Trends Genet.