論文 - 詳細
| RRC ID | 30561 |
|---|---|
| 著者 | Mahyous Saeyd SA, Ewert-Krzemieniewska K, Liu B, Caspari T. |
| タイトル | Hyperactive Cdc2 kinase interferes with the response to broken replication forks by trapping S.pombe Crb2 in its mitotic T215 phosphorylated state. |
| ジャーナル | Nucleic Acids Res |
| Abstract |
Although it is well established that Cdc2 kinase phosphorylates the DNA damage checkpoint protein Crb2(53BP1) in mitosis, the full impact of this modification is still unclear. The Tudor-BRCT domain protein Crb2 binds to modified histones at DNA lesions to mediate the activation of Chk1 by Rad3ATR kinase. We demonstrate here that fission yeast cells harbouring a hyperactive Cdc2CDK1 mutation (cdc2.1w) are specifically sensitive to the topoisomerase 1 inhibitor camptothecin (CPT) which breaks DNA replication forks. Unlike wild-type cells, which delay only briefly in CPT medium by activating Chk1 kinase, cdc2.1w cells bypass Chk1 to enter an extended cell-cycle arrest which depends on Cds1 kinase. Intriguingly, the ability to bypass Chk1 requires the mitotic Cdc2 phosphorylation site Crb2-T215. This implies that the presence of the mitotic phosphorylation at Crb2-T215 channels Rad3 activity towards Cds1 instead of Chk1 when forks break in S phase. We also provide evidence that hyperactive Cdc2.1w locks cells in a G1-like DNA repair mode which favours non-homologous end joining over interchromosomal recombination. Taken together, our data support a model such that elevated Cdc2 activity delays the transition of Crb2 from its G1 to its G2 mode by blocking Srs2 DNA helicase and Casein Kinase 1 (Hhp1). |
| 巻・号 | 42(12) |
| ページ | 7734-47 |
| 公開日 | 2014-7-1 |
| DOI | 10.1093/nar/gku452 |
| PII | gku452 |
| PMID | 24861625 |
| PMC | PMC4081076 |
| MeSH | Antigens, Nuclear / metabolism CDC2 Protein Kinase / genetics CDC2 Protein Kinase / metabolism* Camptothecin / pharmacology Cell Cycle Proteins / chemistry Cell Cycle Proteins / metabolism* Checkpoint Kinase 1 DNA Helicases / metabolism DNA Repair* DNA Replication DNA-Binding Proteins / metabolism G1 Phase / genetics G2 Phase Cell Cycle Checkpoints / genetics* Ku Autoantigen Mitosis / genetics Mutation Nuclear Proteins / chemistry Nuclear Proteins / metabolism* Phosphorylation Protein Kinases / metabolism Schizosaccharomyces / drug effects Schizosaccharomyces / enzymology Schizosaccharomyces / metabolism Schizosaccharomyces pombe Proteins / chemistry Schizosaccharomyces pombe Proteins / genetics Schizosaccharomyces pombe Proteins / metabolism* Topoisomerase I Inhibitors / pharmacology |
| IF | 11.502 |
| 引用数 | 4 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 酵母 | |