Checkpoint-Dependent Regulation of Origin Firing and Replication Fork Movement in Response to DNA Damage in Fission Yeast

Kumar, Sanjay; Huberman, Joel A.

doi:10.1128/mcb.01319-08

Cited by 25 publications

(17 citation statements)

References 57 publications

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“…DNA lesions themselves slow polymerase progression, but in budding yeast this effect was found to be independent of Mec1 and Rad53 122 . The CHK1 homolog in fission yeast, Cds1, was suggested to slow fork movement in response to DNA damage 139 . Similarly, in human cells CHK1 was shown to slow fork elongation rates following camptothecin-induced DNA damage 140,141 .…”

Section: Atr Functions During Dna Replicationmentioning

confidence: 99%

The essential kinase ATR: ensuring faithful duplication of a challenging genome

Saldivar

Chen

Cimprich

2017

Nat Rev Mol Cell Biol

635

695

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One way to preserve a rare book is to lock it away from all potential sources of damage. Of course, an inaccessible book is also of little use, and the paper and ink will continue to degrade with age in any case. Like a book, the information stored in our DNA needs to be read, but it is also subject to continuous assault. In this review, we examine how the replication stress response that is controlled by the kinase ataxia telangiectasia and Rad3-related (ATR) senses and resolves threats to DNA integrity so the DNA remains available to read in all of our cells. We discuss the multiple data that have revealed an elegant yet increasingly complex mechanism of ATR activation. These involve a core set of components that recruit ATR to stressed replication forks, stimulate kinase activity and amplify ATR signaling. We focus on the activities of ATR in control of cell cycle checkpoints, origin firing and replication fork stability, and how proper regulation of these processes is crucial to ensure faithful duplication of a challenging genome.

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Section: Atr Functions During Dna Replicationmentioning

confidence: 99%

The essential kinase ATR: ensuring faithful duplication of a challenging genome

Saldivar

Chen

Cimprich

2017

Nat Rev Mol Cell Biol

635

695

View full text Add to dashboard Cite

show abstract

“…However, our results do not overrule the idea that inhibition of the origin firing near the forks also inhibits fork restart in WRN-WT cells in response to CPT, which warrants further study. Importantly, Kumar and colleagues recently showed the persistence of replication intermediates in MMS-treated fission yeast by using 2D-gel analysis of replication intermediates (Kumar et al, 2009). This suggests the inhibition of fork progress in response to MMS.…”

Section: Discussionmentioning

confidence: 99%

WRN helicase regulates the ATR–CHK1-induced S-phase checkpoint pathway in response to topoisomerase-I–DNA covalent complexes

Patro

Frøhlich

Bohr

et al. 2011

Journal of Cell Science

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SummaryCheckpoints are cellular surveillance and signaling pathways that coordinate the response to DNA damage and replicative stress. Consequently, failure of cellular checkpoints increases susceptibility to DNA damage and can lead to profound genome instability. This study examines the role of a human RECQ helicase, WRN, in checkpoint activation in response to DNA damage. Mutations in WRN lead to genomic instability and the premature aging condition Werner syndrome. Here, the role of WRN in a DNA-damage-induced checkpoint was analyzed in U-2 OS (WRN wild type) and isogenic cells stably expressing WRN-targeted shRNA (WRN knockdown). The results of our studies suggest that WRN has a crucial role in inducing an S-phase checkpoint in cells exposed to the topoisomerase I inhibitor campthothecin (CPT), but not in cells exposed to hydroxyurea. Intriguingly, WRN decreases the rate of replication fork elongation, increases the accumulation of ssDNA and stimulates phosphorylation of CHK1, which releases CHK1 from chromatin in CPT-treated cells. Importantly, knockdown of WRN expression abolished or delayed all these processes in response to CPT. Together, our results strongly suggest an essential regulatory role for WRN in controlling the ATR-CHK1-mediated S-phase checkpoint in CPT-treated cells.

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“…In vitro study with Xenopus egg extracts indicated that the DNA damage checkpoint response induced by MMS was closely correlated with the process of DNA replication, mainly involved in the double-strand breaks in replication forks [28] . The study in S. pombe revealed that the MMS treatment induced S-phase delay through the inhibition of both origin firing and replication fork movements [29] . In the present studies, Comet assay was applied to detect DNA damage in MMS-treated HeLa cells, which showed that the MMS treatment caused DNA strand breaks in HeLa cells (unpublished data; and see ref.…”

Section: Discussionmentioning

confidence: 99%

Chk1 prevents abnormal mitosis of S-phase HeLa cells containing DNA damage

Ward

Yao

et al. 2009

Chin. Sci. Bull.

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To explore effects of DNA damage on cell-cycle progression in p53-deficient tumor cells, synchronized HeLa cells at G1, S and G2/M phases were treated with methyl methanesulfnate (MMS). The resultsshowed that the MMS treatment resulted in the cell-cycle arrest or delay in all 3 phases, while the S-phase cells were the most sensitive to MMS. Further studies demonstrated that ATM-Chk2 and p38 MAPK signaling pathways were activated in all 3 phases when the cells were treated with MMS; whereas Chk1 was activated only in S phase under the drug treatment, indicating that Chk1 specifically participated in S-phase checkpoints. To analyze the role of Chk1 in S-phase checkpoints, we administered a specific Chk1 inhibitor, UCN-01, to the S-phase cells. The results showed that the S-phase cells treated with MMS+UCN-01 could enter aberrant mitosis without finishing DNA replication, indicating that Chk1 mainly functions in the DNA damage checkpoint rather than in the replication checkpoint. In addition, MMS treatment alone inhibited the accumulation of cyclin B1, a key component of M-phase CDK-cyclin complex, in the S-phase cells, whereas the inhibition of Chk1 activation resulted in the accumulation of cyclin B1 in the MMS-treated S-phase cells. This observation further supports the view that DNA-damaged S-phase cells enter abnormal mitosis when Chk1 activation is inhibited. Our results demonstrate that Chk1 is a specific kinase that plays an important role in the MMS-induced S-phase DNA damage checkpoint. As p53 is not involved in this process, Chk1 may be a potential target for p53-deficient tumor therapy. cell cycle, DNA damage checkpoint, DNA replication checkpoint, Chk1, methyl methanesulfnate During the evolutionary process, cells have developed molecular regulatory pathways called checkpoints to control the quality of cell proliferation. There are 3 types of checkpoints: (i) The DNA damage checkpoint responsible for checking DNA damage; (ii) the DNA replication checkpoint checking whether DNA is replicated normally; and (iii) the spindle assembly checkpoint, which checks the quality of chromosome segregation [1,2] .The DNA damage checkpoint is biochemical pathways that delay or arrest cell cycle progression in response to genomic DNA damage. Since DNA damage may occur at any phase of a cell cycle, there exist G1, S and G2/M DNA damage checkpoints respectively. A number of studies have revealed that different molecular mechanisms correspond to DNA damage checkpoints at different phases [3,4] , and ATR/Chk1 and ATM/Chk2 signaling pathways especially play important roles [5] . The ATM/Chk2 pathway is activated when the genome is damaged by DNA double-strand breaks [6] , while the ATR/Chk1 pathway mainly functions in the case of DNA single-stranded breaks (SSB) or structural damage

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Checkpoint-Dependent Regulation of Origin Firing and Replication Fork Movement in Response to DNA Damage in Fission Yeast

Cited by 25 publications

References 57 publications

The essential kinase ATR: ensuring faithful duplication of a challenging genome

The essential kinase ATR: ensuring faithful duplication of a challenging genome

WRN helicase regulates the ATR–CHK1-induced S-phase checkpoint pathway in response to topoisomerase-I–DNA covalent complexes

Chk1 prevents abnormal mitosis of S-phase HeLa cells containing DNA damage

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