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首页> 外文期刊>Molecular cell >Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage.
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Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage.

机译：Cdk1参与响应于DNA损伤的BRCA1依赖性S期检查点控制。

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摘要

Cdk2 and cdk1 are individually dispensable for cell-cycle progression in cancer cell lines because they are able to compensate for one another. However, shRNA-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated S phase cell-cycle arrest and the phosphorylation of a subset of ATR/ATM targets after DNA damage. Loss of DNA damage-induced checkpoint control was caused by a reduction in formation of BRCA1-containing foci. Mutation of BRCA1 at S1497 and S1189/S1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of BRCA1-containing foci. Abrogation of checkpoint control after cdk1 depletion or inhibition in non-small-cell lung cancer cells sensitized them to DNA-damaging agents. Conversely, reduced cdk1 activity caused more potent G2/M arrest in nontransformed cells and antagonized the response to subsequent DNA damage. Cdk1 inhibition may therefore selectively sensitize BRCA1-proficient cancer cells to DNA-damaging treatments by disrupting BRCA1 function.
机译：Cdk2和cdk1可单独分配给癌细胞系中的细胞周期进程，因为它们能够相互补偿。然而，shRNA介导的cdk1单独耗尽或小分子cdk1抑制消除了DNA损伤后S期细胞周期停滞和一部分ATR / ATM靶的磷酸化。 DNA损伤诱导的检查点控制的丧失是由于含BRCA1灶的形成减少所致。在S1497和S1189 / S1191处BRCA1的突变导致cdk1介导的磷酸化的丧失，也损害了含BRCA1的灶的形成。 cdk1耗尽或抑制后，非小细胞肺癌细胞中检查点控制的废止使它们对DNA破坏剂敏感。相反，降低的cdk1活性导致未转化细胞中更有效的G2 / M阻滞，并拮抗对随后DNA损伤的反应。因此，Cdk1抑制作用可能会通过破坏BRCA1功能选择性地使BRCA1熟练的癌细胞对DNA损伤的治疗敏感。

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