hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response
hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response
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DOI：
10.1038/35004614
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发表时间：
2000-03-09
期刊：
影响因子：
64.8
通讯作者：
Chung, JH
中科院分区：
文献类型：
--
作者：
Lee, JS;Collins, KM;Chung, JH
BRCA 1（参考文献1）肿瘤抑制基因突变在几乎所有遗传性乳腺癌和卵巢癌家族中发现，约一半的家族仅患有乳腺癌（2，3）。虽然BRCA 1的生物化学功能还不清楚，但它对DNA损伤修复（4-7）和细胞周期检查点（8-10）很重要。BRCA 1存在于核灶中，但在DNA损伤后过度磷酸化并分散（11，12）。目前尚不清楚BRCA 1磷酸化和分散与其在DNA损伤反应中的功能是否相关。在酵母中，DNA损伤反应和复制阻断检查点部分通过Cds 1激酶家族介导（13-20）。在这里，我们报告了人Cds 1激酶（hCds 1/Chk 2）（21-23）通过磷酸化BRCA 1的丝氨酸988来调节DNA损伤后BRCA 1的功能。我们发现，hCds 1和BRCA 1相互作用和共定位在离散的核灶，但分开后，γ射线照射。BRCA 1在丝氨酸988处的磷酸化是BRCA 1从hCds 1释放所必需的。这种磷酸化对于BRCA 1在BRCA 1突变细胞系HCC 1937中DNA损伤后恢复存活的能力也很重要。
Mutations in the BRCA1 (ref. 1) tumour suppressor gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer(2,3). Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage repair(4-7) and cell-cycle checkpoints(8-10). BRCA1 exists in nuclear foci but is hyperphosphorylated and disperses after DNA damage(11,12). It is not known whether BRCA1 phosphorylation and dispersion and its function in DNA damage response are related. In yeast the DNA damage response and the replication-block checkpoint are mediated partly through the Cds1 kinase family(13-20). Here we report that the human Cds1 kinase (hCds1/Chk2)(21-23) regulates BRCA1 function after DNA damage by phosphorylating serine 988 of BRCA1. We show that hCds1 and BRCA1 interact and colocalize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine 988 is required for the release of BRCA1 from hCds1. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937.