The intra-S phase checkpoint targets Dna2 to prevent stalled replication forks from reversing

When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In intra-S checkpoint-deficient budding yeast, stalling forks collapse, and ∼10% form pathogenic chicken foot structures, contributing to incomplete r...

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Vydáno v:Cell Ročník 149; číslo 6; s. 1221
Hlavní autoři: Hu, Jiazhi, Sun, Lei, Shen, Fenfen, Chen, Yufei, Hua, Yu, Liu, Yang, Zhang, Mian, Hu, Yiren, Wang, Qingsong, Xu, Wei, Sun, Fei, Ji, Jianguo, Murray, Johanne M, Carr, Antony M, Kong, Daochun
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 08.06.2012
Témata:
Checkpoint Kinase 2
DNA Replication
Epistasis, Genetic
Flap Endonucleases - metabolism
Genomic Instability
Phosphorylation
Protein Serine-Threonine Kinases - metabolism
S Phase Cell Cycle Checkpoints
Schizosaccharomyces - cytology
Schizosaccharomyces - genetics
Schizosaccharomyces - metabolism
Schizosaccharomyces pombe Proteins - metabolism
ISSN:1097-4172, 1097-4172
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Popis
Shrnutí:When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In intra-S checkpoint-deficient budding yeast, stalling forks collapse, and ∼10% form pathogenic chicken foot structures, contributing to incomplete replication and cell death (Lopes et al., 2001; Sogo et al., 2002; Tercero and Diffley, 2001). Using fission yeast, we report that the Cds1(Chk2) effector kinase targets Dna2 on S220 to regulate, both in vivo and in vitro, Dna2 association with stalled replication forks in chromatin. We demonstrate that Dna2-S220 phosphorylation and the nuclease activity of Dna2 are required to prevent fork reversal. Consistent with this, Dna2 can efficiently cleave obligate precursors of fork regression-regressed leading or lagging strands-on model replication forks. We propose that Dna2 cleavage of regressed nascent strands prevents fork reversal and thus stabilizes stalled forks to maintain genome stability during replication stress.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2012.04.030