细胞周期蛋白依赖性激酶1（Cdk1）参与响应DNA损伤的BRCA1依赖性S期检查点控制。
Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage.
作者信息
Johnson Neil, Cai Dongpo, Kennedy Richard D, Pathania Shailja, Arora Mansi, Li Yu-Chen, D'Andrea Alan D, Parvin Jeffrey D, Shapiro Geoffrey I
机构信息
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
出版信息
Mol Cell. 2009 Aug 14;35(3):327-39. doi: 10.1016/j.molcel.2009.06.036.
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.
在癌细胞系中，Cdk2和Cdk1对于细胞周期进程而言各自并非必需，因为它们能够相互补偿。然而，单独通过shRNA介导的Cdk1缺失或小分子Cdk1抑制会消除DNA损伤后S期细胞周期阻滞以及一部分ATR/ATM靶点的磷酸化。DNA损伤诱导的检查点控制丧失是由含BRCA1的病灶形成减少所致。BRCA1在S1497以及S1189/S1191处的突变导致Cdk1介导的磷酸化丧失，并且也损害了含BRCA1的病灶形成。在非小细胞肺癌细胞中，Cdk1缺失或抑制后检查点控制的废除使它们对DNA损伤剂敏感。相反，Cdk1活性降低在未转化细胞中导致更有效的G2/M期阻滞，并拮抗对后续DNA损伤的反应。因此，Cdk1抑制可能通过破坏BRCA1功能而选择性地使BRCA1功能正常的癌细胞对DNA损伤治疗敏感。
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