Pathways governing G1/S transition and their response to DNA damage.
The ability to self-replicate is a fundamental feature of life, reflected at the cellular level by a highly regulated process initiated in G1 phase via commitment to a round of DNA replication and cell division. Here we briefly highlight recent advances in understanding the molecular pathways which govern the decision of mammalian somatic cells to enter S phase, and the so-called cell cycle checkpoints which guard the G1/S transition and S phase progression against potentially deleterious effects of genotoxic stress. Particular emphasis is put on the emerging parallel yet cooperative pathways of retinoblastoma protein (pRB)-E2F and Myc, their convergence to control the activity of the cyclin-dependent kinase 2 (Cdk2) at the G1/S boundary, as well as the two waves of checkpoint responses at G1/S: the rapid pathway(s) leading to Cdc25A degradation, and the delayed p53-p21 cascade, both silencing the Cdk2 activity upon DNA damage.
Bartek
J
J
Department of Cell Cycle and Cancer, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark. bartek@biobase.dk
Lukas
J
J
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016193:G1 Phase; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases