Coupling of DNA replication and mitosis by fission yeast rad4/cut5

Saka, Yasushi; Fantes, Peter A.; Yanagida, Mitsuhiro

doi:10.1242/jcs.1994.supplement_18.8

Cited by 20 publications

(10 citation statements)

References 30 publications

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“…dpb11-1 mutant cells are sensitive to HU, defective in DNA synthesis at the restrictive temperature, and display uneven distribution of genetic material (9). These phenotypes suggest that dpb11-1 mutant cells are defective in the DNA replication checkpoint like mutants in their fission yeast homolog cut5 (18). Although consistent with a checkpoint defect, spindle elongation studies in the absence of completed DNA replication and other indicators of checkpoint function were not analyzed (9) and are required to definitively demonstrate a checkpoint role for DPB11.…”

Section: Resultsmentioning

confidence: 99%

DRC1, DNA replication and checkpoint protein 1, functions with DPB11 to control DNA replication and the S-phase checkpoint in Saccharomyces cerevisiae

Wang

Elledge

1999

Proc. Natl. Acad. Sci. U.S.A.

120

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In addition to DNA polymerase complexes, DNA replication requires the coordinate action of a series of proteins, including regulators Cdc28͞Clb and Dbf4͞Cdc7 kinases, Orcs, Mcms, Cdc6, Cdc45, and Dpb11. Of these, Dpb11, an essential BRCT repeat protein, has remained particularly enigmatic. The Schizosaccharomyces pombe homolog of DPB11, cut5, has been implicated in the DNA replication checkpoint as has the POL2 gene with which DPB11 genetically interacts. Here we describe a gene, DRC1, isolated as a dosage suppressor of dpb11-1. DRC1 is an essential cell cycle-regulated gene required for DNA replication. We show that both Dpb11 and Drc1 are required for the S-phase checkpoint, including the proper activation of the Rad53 kinase in response to DNA damage and replication blocks. Dpb11 is the second BRCT-repeat protein shown to control Rad53 function, possibly indicating a general function for this class of proteins. DRC1 and DPB11 show synthetic lethality and reciprocal dosage suppression. The Drc1 and Dpb11 proteins physically associate and function together to coordinate DNA replication and the cell cycle.

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Section: Resultsmentioning

confidence: 99%

DRC1, DNA replication and checkpoint protein 1, functions with DPB11 to control DNA replication and the S-phase checkpoint in Saccharomyces cerevisiae

Wang

Elledge

1999

Proc. Natl. Acad. Sci. U.S.A.

120

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“…1B, right), which produced expected sizes of the EcoT22I fragments for the mutant genomic DNAs. The T45M mutation resided in the middle of the first amino-terminal repeat R1 (consensus is indicated in the bottom of panel A; Saka et al 1994b). T45 is present within the conserved stretch (consensus, VTHLIA), hereafter designated as the TH domain.…”

Section: Mutations Of Cut5/rad4 In the Conserved Amino-terminusmentioning

confidence: 99%

Damage and replication checkpoint control in fission yeast is ensured by interactions of Crb2, a protein with BRCT motif, with Cut5 and Chk1

Saka¹,

Esashi²,

Matsusaka³

et al. 1997

Genes Dev.

Self Cite

240

296

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Fission yeast Cut5/Rad4 plays a unique role in the genome maintenance as it is required for replication, replication checkpoint, and normal UV sensitivity. It is unknown, however, how Cut5 protein is linked to other checkpoint proteins, and what part it plays in replication and UV sensitivity. Here we report that Cut5 interacts with a novel checkpoint protein Crb2 and that this interaction is needed for normal genome maintenance. The carboxyl terminus of Crb2 resembles yeast Rad9 and human 53BP1 and BRCA1. Crb2 is required for checkpoint arrests induced by irradiation and polymerase mutations, but not for those induced by inhibited nucleotide supply. Upon UV damage, Crb2 is transiently modified, probably phosphorylated, with a similar timing of phosphorylation in Chk1 kinase, which is reported to restrain Cdc2 activation. Crb2 modification requires other damage-sensing checkpoint proteins but not Chk1, suggesting that Crb2 acts at the upstream of Chk1. The modified Crb2 exists as a slowly sedimenting form, whereas Crb2 in undamaged cells is in a rapidly sedimenting structure. Cut5 and Crb2 interact with Chk1 in a two-hybrid system. Moreover, moderate overexpression of Chk1 suppresses the phenotypes of cut5 and crb2 mutants. Cut5, Crb2, and Chk1 thus may form a checkpoint sensor-transmitter pathway to arrest the cell cycle.

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“…While the biological significance of TopBP1-topoisomerase II interaction remains to be resolved, TopBP1 shares sequence and structural similarities with the fission yeast Rad4/Cut5 protein. Rad4/Cut5 is a checkpoint Rad protein involved in cellular responses to DNA damage and replication blocks (22,40,(47)(48)(49)(50)60). Genetic and biochemical studies suggest that Schizosaccharomyces pombe Rad4/Cut5 (pRad4/Cut5) and its associated protein spCrb2 interact with the checkpoint kinase spChk1 and act upstream of spChk1 in the checkpoint signaling pathway (47).…”

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confidence: 99%

A DNA Damage-Regulated BRCT-Containing Protein, TopBP1, Is Required for Cell Survival

Yamane

Chen

2002

Molecular and Cellular Biology

174

179

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BRCA1 carboxyl-terminal (BRCT) motifs are present in a number of proteins involved in DNA repair and/or DNA damage-signaling pathways. Human DNA topoisomerase II binding protein 1 (TopBP1) contains eight BRCT motifs and shares sequence similarity with the fission yeast Rad4/Cut5 protein and the budding yeast DPB11 protein, both of which are required for DNA damage and/or replication checkpoint controls. We report here that TopBP1 is phosphorylated in response to DNA double-strand breaks and replication blocks. TopBP1 forms nuclear foci and localizes to the sites of DNA damage or the arrested replication forks. In response to DNA strand breaks, TopBP1 phosphorylation depends on the ataxia telangiectasia mutated protein (ATM) in vivo. However, ATM-dependent phosphorylation of TopBP1 does not appear to be required for focus formation following DNA damage. Instead, focus formation relies on one of the BRCT motifs, BRCT5, in TopBP1. Antisense Morpholino oligomers against TopBP1 greatly reduced TopBP1 expression in vivo. Similar to that of ataxia telangiectasia-related protein (ATR), Chk1, or Hus1, downregulation of TopBP1 leads to reduced cell survival, probably due to increased apoptosis. Taken together, the data presented here suggest that, like its putative counterparts in yeast species, TopBP1 may be involved in DNA damage and replication checkpoint controls.Cell cycle checkpoints induced by DNA damage are essential for maintaining genetic integrity. Signals of DNA damage lead to cell cycle arrest and allow time for the repair of damaged DNA (for recent reviews, see references 41, 45, and 72). Failure of checkpoint responses results in genetic instability, frequently leading to cancer development.In mammals, ataxia telangiectasia mutated protein (ATM) and ataxia telangiectasia-related protein (ATR), two phosphatidylinositol-3 kinase (PI3K)-related protein kinases, are essential components in DNA damage-signaling pathways. In response to DNA damage and/or replication blocks, ATM and ATR activate the downstream checkpoint kinases Chk1 and Chk2/Cds1 (see references 41, 45, and 72 for details). Together, these four DNA damage-activated kinases phosphorylate and regulate a number of proteins, including Cdc25C (4,7,13,35,39,51), Cdc25A (21,36), NBS1 (24,34,65,70), p53 (3,11,14,28,31,55,58), BRCA1 (15,17,23,25,32,59), and CtIP (33). By regulating the functions of these proteins and other unidentified substrates, these kinases play essential roles in coordinating DNA repair, cell cycle progression, transcriptional regulation, and apoptosis in response to various DNAdamaging events.In order to understand in detail the mammalian DNA damage-signaling pathway, one has to identify the physiological substrates of ATM and ATR. It is interesting that several ATM and/or ATR substrates, including BRCA1 and NBS1, contain BRCA1 carboxyl-terminal (BRCT) motifs. BRCT motifs were originally identified in the breast cancer tumor suppressor protein BRCA1 (30) and have since been identified in a number of proteins involved in DNA repair (...

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Coupling of DNA replication and mitosis by fission yeast rad4/cut5

Cited by 20 publications

References 30 publications

DRC1, DNA replication and checkpoint protein 1, functions with DPB11 to control DNA replication and the S-phase checkpoint in Saccharomyces cerevisiae

DRC1, DNA replication and checkpoint protein 1, functions with DPB11 to control DNA replication and the S-phase checkpoint in Saccharomyces cerevisiae

Damage and replication checkpoint control in fission yeast is ensured by interactions of Crb2, a protein with BRCT motif, with Cut5 and Chk1

A DNA Damage-Regulated BRCT-Containing Protein, TopBP1, Is Required for Cell Survival

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