The G2-phase DNA-damage checkpoint.

DNA damage causes cell-cycle delay before S phase, during replication and before mitosis. This involves a number of highly conserved proteins that sense DNA damage and signal the cell-cycle machinery. Kinases that were initially discovered in yeast model systems have recently been shown to regulate the regulators of cyclin-dependent kinases and to control the stability of p53. This shows the importance of checkpoint proteins for maintaining genome stability. Here, we discuss recent data from yeast and metazoans that suggest a remarkable conservation of the organization of the G2 DNA-damage checkpoint pathway.

[1]  M. Yanagida,et al.  Damage and replication checkpoint control in fission yeast is ensured by interactions of Crb2, a protein with BRCT motif, with Cut5 and Chk1. , 1997, Genes & development.

[2]  N. Walworth,et al.  S-phase-specific activation of Cds1 kinase defines a subpathway of the checkpoint response in Schizosaccharomyces pombe. , 1998, Genes & development.

[3]  P. Russell,et al.  Nuclear localization of Cdc25 is regulated by DNA damage and a 14-3-3 protein , 1999, Nature.

[4]  H. Erdjument-Bromage,et al.  A novel Rad24 checkpoint protein complex closely related to replication factor C , 2000, Current Biology.

[5]  A. Carr,et al.  Characterisation of the Schizosaccharomyces pombe rad4/cut5 mutant phenotypes: dissection of DNA replication and G2 checkpoint control function , 1997, Molecular and General Genetics MGG.

[6]  S. Elledge,et al.  Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. , 1997, Science.

[7]  A. Kumagai,et al.  Binding of 14-3-3 proteins and nuclear export control the intracellular localization of the mitotic inducer Cdc25. , 1999, Genes & development.

[8]  P. Nurse Universal control mechanism regulating onset of M-phase , 1990, Nature.

[9]  S. Osmani,et al.  Checkpoint defects leading to premature mitosis also cause endoreplication of DNA in Aspergillus nidulans. , 1999, Molecular biology of the cell.

[10]  M. Lovett,et al.  A single ataxia telangiectasia gene with a product similar to PI-3 kinase. , 1995, Science.

[11]  S. Elledge,et al.  DNA polymerase ϵ links the DNA replication machinery to the S phase checkpoint , 1995, Cell.

[12]  N. Walworth,et al.  Association of Chk1 with 14-3-3 proteins is stimulated by DNA damage. , 1999, Genes & development.

[13]  A. Carr Control of cell cycle arrest by the Mec1sc/Rad3sp DNA structure checkpoint pathway. , 1997, Current opinion in genetics & development.

[14]  H. Piwnica-Worms,et al.  DNA Damage and Replication Checkpoints in Fission Yeast Require Nuclear Exclusion of the Cdc25 Phosphatase via 14-3-3 Binding , 1999, Molecular and Cellular Biology.

[15]  D. Morgan,et al.  Nuclear Localization of Cyclin B1 Controls Mitotic Entry After DNA Damage , 1998, The Journal of cell biology.

[16]  A. Carr,et al.  A Rad3–Rad26 complex responds to DNA damage independently of other checkpoint proteins , 1999, Nature Cell Biology.

[17]  J. Willson,et al.  Isolation and characterization of the Schizosaccharomyces pombe rhp9 gene: a gene required for the DNA damage checkpoint but not the replication checkpoint. , 1997, Nucleic acids research.

[18]  D. Morgan,et al.  Role of inhibitory CDC2 phosphorylation in radiation-induced G2 arrest in human cells , 1996, The Journal of cell biology.

[19]  C. Rieder,et al.  Entry into Mitosis in Vertebrate Somatic Cells Is Guarded by a Chromosome Damage Checkpoint That Reverses the Cell Cycle When Triggered during Early but Not Late Prophase , 1998, The Journal of cell biology.

[20]  K. Kinzler,et al.  Requirement for p53 and p21 to sustain G2 arrest after DNA damage. , 1998, Science.

[21]  A. Carr,et al.  Mik1 levels accumulate in S phase and may mediate an intrinsic link between S phase and mitosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Moreno,et al.  Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1 , 1998, Nature.

[23]  A. Carr,et al.  DNA repair mutants defining G2 checkpoint pathways in Schizosaccharomyces pombe. , 1992, The EMBO journal.

[24]  T. Caspari,et al.  Characterization of Schizosaccharomyces pombeHus1: a PCNA-Related Protein That Associates with Rad1 and Rad9 , 2000, Molecular and Cellular Biology.

[25]  A. Kumagai,et al.  The Xenopus Chk1 Protein Kinase Mediates a Caffeine-sensitive Pathway of Checkpoint Control in Cell-free Extracts , 1998, The Journal of cell biology.

[26]  X. Wang,et al.  Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. , 1999, Molecular cell.

[27]  A. Carr,et al.  Protein kinase mutants of human ATR increase sensitivity to UV and ionizing radiation and abrogate cell cycle checkpoint control. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Yanagida,et al.  Cdc2 phosphorylation of Crb2 is required for reestablishing cell cycle progression after the damage checkpoint. , 1999, Molecular cell.

[29]  R. Bernards,et al.  rad-Dependent Response of the chk1-Encoded Protein Kinase at the DNA Damage Checkpoint , 1996, Science.

[30]  J. Soulier,et al.  The BRCT domain of the S. cerevisiae checkpoint protein Rad9 mediates a Rad9–Rad9 interaction after DNA damage , 1999, Current Biology.

[31]  K. Tamai,et al.  Replication factor C3 of Schizosaccharomyces pombe, a small subunit of replication factor C complex, plays a role in both replication and damage checkpoints. , 1999, Molecular biology of the cell.

[32]  Č. Venclovas,et al.  A Sliding Clamp Model for the Rad1 Family of Cell Cycle Checkpoint Proteins , 1999, Cell.

[33]  K. Onel,et al.  The REC1 gene of Ustilago maydis, which encodes a 3'-->5' exonuclease, couples DNA repair and completion of DNA synthesis to a mitotic checkpoint. , 1996, Genetics.

[34]  S. Elledge,et al.  Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. , 1999, Science.

[35]  D. Lydall,et al.  Yeast Checkpoint Genes in DNA Damage Processing: Implications for Repair and Arrest , 1995, Science.

[36]  J. Newport,et al.  Coupling of mitosis to the completion of S phase through Cdc34-mediated degradation of Wee1. , 1998, Science.

[37]  S. Osmani,et al.  Two S‐phase checkpoint systems, one involving the function of both BIME and Tyr15 phosphorylation of p34cdc2, inhibit NIMA and prevent premature mitosis. , 1996, The EMBO journal.

[38]  A. Parker,et al.  A Human Homologue of the Schizosaccharomyces pombe rad1 + Checkpoint Gene Encodes an Exonuclease* , 1998, The Journal of Biological Chemistry.

[39]  A. Carr,et al.  Analysis of Rad3 and Chk1 protein kinases defines different checkpoint responses , 1998, The EMBO journal.

[40]  J. Raleigh,et al.  The G(2) DNA damage checkpoint targets both Wee1 and Cdc25. , 2000, Journal of cell science.

[41]  A. Carr,et al.  Feedback controls and G2 checkpoints: Fission yeast as a model system , 1993, BioEssays : news and reviews in molecular, cellular and developmental biology.

[42]  A. Carr,et al.  Fission yeast rad17: a homologue of budding yeast RAD24 that shares regions of sequence similarity with DNA polymerase accessory proteins. , 1995, The EMBO journal.

[43]  T. Hunter,et al.  Cyclin-dependent Kinases Are Inactivated by a Combination of p21 and Thr-14/Tyr-15 Phosphorylation after UV-induced DNA Damage* , 1996, The Journal of Biological Chemistry.

[44]  S. Jackson,et al.  The DNA-dependent protein kinase , 1999 .

[45]  M. O'Connell,et al.  Cut5 is a component of the UV-responsive DNA damage checkpoint in fission yeast , 1998, Molecular and General Genetics MGG.

[46]  P. Nurse,et al.  Meiotic DNA replication checkpoint control in fission yeast. , 1999, Genes & development.

[47]  K. Kinzler,et al.  14-3-3σ is required to prevent mitotic catastrophe after DNA damage , 1999, Nature.

[48]  J. Vialard,et al.  The budding yeast Rad9 checkpoint protein is subjected to Mec1/Tel1‐dependent hyperphosphorylation and interacts with Rad53 after DNA damage , 1998, The EMBO journal.

[49]  P. Nurse,et al.  Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation , 1997, The EMBO journal.

[50]  The role of inhibitory phosphorylation of CDC2 following DNA replication block and radiation-induced damage in human cells. , 1997, Molecular biology of the cell.

[51]  H. Wang,et al.  Control of the DNA damage checkpoint by chk1 and rad53 protein kinases through distinct mechanisms. , 1999, Science.

[52]  P. Russell,et al.  Replication checkpoint enforced by kinases Cds1 and Chk1. , 1998, Science.

[53]  D. Baltimore,et al.  ATR disruption leads to chromosomal fragmentation and early embryonic lethality. , 2000, Genes & development.

[54]  E. Nishida,et al.  Nuclear export of cyclin B1 and its possible role in the DNA damage‐induced G2 checkpoint , 1998, The EMBO journal.

[55]  M. Yanagida,et al.  Fission yeast cut5 +, required for S phase onset and M phase restraint, is identical to the radiation-damage repair gene rad4 + , 1993, Cell.

[56]  N. Rhind,et al.  Cdc2 tyrosine phosphorylation is required for the DNA damage checkpoint in fission yeast. , 1997, Genes & development.

[57]  M. Nakanishi,et al.  Cell cycle-dependent and ATM-independent expression of human Chk1 kinase , 1999, Oncogene.

[58]  A. Carr,et al.  Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice , 2000, Current Biology.

[59]  D. Stern,et al.  Rad53 FHA domain associated with phosphorylated Rad9 in the DNA damage checkpoint. , 1998, Science.

[60]  N. Rhind,et al.  Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase. , 1997, Science.