A single unbranched S-phase DNA damage and replication fork blockage checkpoint pathway

Marchetti, Maria A.; Kumar, Sanjay; Hartsuiker, Edgar; Maftahi, Mohamed; Carr, Antony; Freyer, Greg A.; Burhans, William C.; Huberman, Joel A.

doi:10.1073/pnas.112702399

Cited by 67 publications

(58 citation statements)

References 59 publications

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“…In S. pombe, most checkpoint studies have been carried out with the temperature-sensitive rad4 -116 allele of Rad4/ Cut5, the ortholog of S. cerevisiae Dpb11 and metazoan TopBP1. The central importance attributed to Rad4 in the intra S phase checkpoint in S. pombe could possibly in part be a consequence of defective replisome assembly, which may cause indirectly a defect in activation of Rad3 (ortholog of Mec1) (42). And although several other Rad4 mutants have been studied with various defects in DNA replication and checkpoint function (43), to our knowledge no Rad4/Cut5 mutants have been isolated that affect the C-terminal domain in which the Rad3-activation domain likely resides.…”

Section: Discussionmentioning

confidence: 99%

The Unstructured C-terminal Tail of Yeast Dpb11 (Human TopBP1) Protein Is Dispensable for DNA Replication and the S Phase Checkpoint but Required for the G2/M Checkpoint

Navadgi-Patil¹,

Kumar²,

Burgers

2011

Journal of Biological Chemistry

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Background: Specific activators turn on Mec1/ATR kinase during DNA damage or replication stress, mediating cell cycle arrest. Results: We have separated the replication function of multifunctional Dpb11 from its checkpoint activation function. Conclusion: Dpb11 functions primarily during the G 2 /M phase. Significance: Our results suggest that each phase of the cell cycle may use specific Mec1 activators.

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Section: Discussionmentioning

confidence: 99%

The Unstructured C-terminal Tail of Yeast Dpb11 (Human TopBP1) Protein Is Dispensable for DNA Replication and the S Phase Checkpoint but Required for the G2/M Checkpoint

Navadgi-Patil¹,

Kumar²,

Burgers

2011

Journal of Biological Chemistry

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“…As described under "Materials and Methods," G 1 -arrested cells were released into media containing 20 M CPT or 0.033% MMS. MMS is known to activate the intra-S-phase checkpoint by interfering with progression of replication fork progression (14,47,48), whereas CTP fails to do so (42). DNA was purified from the samples taken at regular (20 or 30 min) intervals after release.…”

Section: Unimpeded S-phase Progression Is Observed In Dna2⌬405n Follomentioning

confidence: 99%

The N-terminal 45-kDa Domain of Dna2 Endonuclease/Helicase Targets the Enzyme to Secondary Structure DNA

Lee

Kang

et al. 2013

Journal of Biological Chemistry

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Background:The biochemical function of variable N-terminal regions of eukaryotic Dna2 remains unclear. Results: The N-terminal 45-kDa domain of yeast Dna2 targets the enzyme specifically to a secondary structure flap. Conclusion:The hairpin binding activity of Dna2 contributes to efficient removal of hairpin flaps together with endonuclease and helicase activities during Okazaki fragment processing. Significance: The hairpin binding activity of Dna2 is critical for genome stability.

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“…This results in Cds1-dependent slowing of DNA replication forks (Lindsay et al 1998;Marchetti et al 2002). However, Dcds1 mutants are only modestly sensitive to MMS treatment (Lindsay et al 1998;Marchetti et al 2002), suggesting at least partial independence from the replication checkpoint. In contrast, hsk1 and dfp1 C-terminal mutants are extremely MMS sensitive (Snaith et al 2000;Takeda et al 2001;Fung et al 2002;Matsumoto et al 2005;Sommariva et al 2005).…”

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confidence: 99%

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confidence: 99%

Fission Yeast Hsk1 (Cdc7) Kinase Is Required After Replication Initiation for Induced Mutagenesis and Proper Response to DNA Alkylation Damage

Dolan

Schmidt

et al. 2010

Genetics

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Genome stability in fission yeast requires the conserved S-phase kinase Hsk1 (Cdc7) and its partner Dfp1 (Dbf4). In addition to their established function in the initiation of DNA replication, we show that these proteins are important in maintaining genome integrity later in S phase and G2. hsk1 cells suffer increased rates of mitotic recombination and require recombination proteins for survival. Both hsk1 and dfp1 mutants are acutely sensitive to alkylation damage yet defective in induced mutagenesis. Hsk1 and Dfp1 are associated with the chromatin even after S phase, and normal response to MMS damage correlates with the maintenance of intact Dfp1 on chromatin. A screen for MMS-sensitive mutants identified a novel truncation allele, rad35 (dfp1-(1-519)), as well as alleles of other damage-associated genes. Although Hsk1-Dfp1 functions with the Swi1-Swi3 fork protection complex, it also acts independently of the FPC to promote DNA repair. We conclude that Hsk1-Dfp1 kinase functions post-initiation to maintain replication fork stability, an activity potentially mediated by the C terminus of Dfp1.T HE Hsk1 protein kinase, the fission yeast ortholog of Saccharomyces cerevisiae Cdc7, is a conserved protein essential for the initiation of DNA replication (Masai et al. 1995;Brown and Kelly 1998;Snaith et al. 2000). Data from many systems suggest that the kinase functions at individual replication origins to activate the prereplication complex (preRC) through phosphorylation of the MCM helicase and other subunits (reviewed in Forsburg 2004). In fission yeast, Hsk1 kinase activity is limited to S phase by its regulatory subunit Dfp1, which is transcriptionally and posttranslationally regulated to restrict its peak of activity to S phase (Brown and Kelly 1999;Takeda et al. 1999). The requirement for Dfp1 (in S. cerevisiae, Dbf4) is similar to the dependence of CDK kinases on cyclin activity; thus, the Ccd7 kinase family has been dubbed DDK (Dbf4-dependent kinases) ( Johnston et al. 1999;Duncker and Brown 2003). Hsk1 is a target of the Cds1 checkpoint kinase and undergoes Cds1-dependent phosphorylation during hydroxyurea (HU) treatment in vivo and in vitro (Snaith et al. 2000). Interestingly, deletion of Dcds1 partly rescues hsk1-1312 temperature sensitivity, which suggests that Hsk1 is negatively regulated by the replication checkpoint. In turn, Cds1 is poorly activated in hsk1 mutants after HU treatment, indicating that there may be a feedback loop linking these two kinases (Snaith et al. 2000;Takeda et al. 2001). hsk1 mutants are sensitive to HU treatment, with a phenotype suggesting a specific defect in recovery (Snaith et al. 2000).DDK kinases have substrates outside of the replication initiation pathway. Functional dissection of Schizosaccaromyces pombe Dfp1 identifies separate regions that are required for checkpoint response (N-terminal domain; Takeda et al. 1999;Fung et al. 2002), for centromere cohesion and replication (MIR domain;Bailis et al. 2003;Hayashi et al. 2009) and for proper response to alkylat...

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A single unbranched S-phase DNA damage and replication fork blockage checkpoint pathway

Cited by 67 publications

References 59 publications

The Unstructured C-terminal Tail of Yeast Dpb11 (Human TopBP1) Protein Is Dispensable for DNA Replication and the S Phase Checkpoint but Required for the G2/M Checkpoint

The Unstructured C-terminal Tail of Yeast Dpb11 (Human TopBP1) Protein Is Dispensable for DNA Replication and the S Phase Checkpoint but Required for the G2/M Checkpoint

The N-terminal 45-kDa Domain of Dna2 Endonuclease/Helicase Targets the Enzyme to Secondary Structure DNA

Fission Yeast Hsk1 (Cdc7) Kinase Is Required After Replication Initiation for Induced Mutagenesis and Proper Response to DNA Alkylation Damage

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