Roles of Kruppel-associated Box (KRAB)-associated Co-repressor KAP1 Ser-473 Phosphorylation in DNA Damage Response
Roles of Kruppel-associated Box (KRAB)-associated Co-repressor KAP1 Ser-473 Phosphorylation in DNA Damage Response
复制标题
Kruppel 相关盒 (KRAB) 相关辅阻遏物 KAP1 Ser-473 磷酸化在 DNA 损伤反应中的作用
DOI：
10.1074/jbc.m111.313262
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发表时间：
2012-06-01
影响因子：
4.8
通讯作者：
Wang, Chuangui
中科院分区：
文献类型：
--
作者：
Hu, Chen;Zhang, Shengping;Wang, Chuangui
Kruppel相关盒（KRAB）相关的共阻遏物KAP 1是转录因子KRAB锌指蛋白超家族的必需核共阻遏物。共济失调毛细血管扩张突变型（ATM）-Chk 2和ATM-和Rad 3-相关型（ATR）-Chk 1是响应于DNA损伤而激活的两个主要激酶信号级联。越来越多的证据表明，ATM和ATR磷酸化KAP 1在Ser-824响应DNA损伤和调节KAP 1依赖的染色质凝聚，DNA修复和基因表达。在这里，我们表明，根据发生的DNA损伤的类型，KAP 1 Ser-473可以被ATM-Chk 2或ATR-Chk 1激酶磷酸化。KAP 1在Ser-473的磷酸化减弱了其与异染色质蛋白1家族蛋白的结合，并抑制了其对KRAB-锌指蛋白（KRAB-ZFP）靶基因的转录抑制。此外，DNA损伤诱导的KAP 1 Ser-473磷酸化刺激KAP 1-E2 F1结合。异染色质蛋白1的过表达显著抑制E2 F1-KAP 1结合。KAP 1 Ser-473磷酸化的消除增加了E2 F1靶向的促凋亡基因表达和E2 F1诱导的细胞凋亡对DNA损伤的反应。此外，KAP 1 Ser-473磷酸化的丧失导致BRCA 1病灶形成较少，并且DNA损伤后γ H2 AX病灶丧失的动力学较慢。KAP 1 Ser-473磷酸化是有效的DNA修复和细胞存活所必需的。我们的研究揭示了压力下KAP 1 Ser-473磷酸化的新功能。
The Kruppel-associated box (KRAB)-associated co-repressor KAP1 is an essential nuclear co-repressor for the KRAB zinc finger protein superfamily of transcriptional factors. Ataxia telangiectasia mutated (ATM)-Chk2 and ATM- and Rad3-related (ATR)-Chk1 are two primary kinase signaling cascades activated in response to DNA damage. A growing body of evidence suggests that ATM and ATR phosphorylate KAP1 at Ser-824 in response to DNA damage and regulate KAP1-dependent chromatin condensation, DNA repair, and gene expression. Here, we show that, depending on the type of DNA damage that occurs, KAP1 Ser-473 can be phosphorylated by ATM-Chk2 or ATR-Chk1 kinases. Phosphorylation of KAP1 at Ser-473 attenuated its binding to the heterochromatin protein 1 family proteins and inhibited its transcriptional repression of KRAB-zinc finger protein (KRAB-ZFP) target genes. Moreover, KAP1 Ser-473 phosphorylation induced by DNA damage stimulated KAP1-E2F1 binding. Overexpression of heterochromatin protein 1 significantly inhibited E2F1-KAP1 binding. Elimination of KAP1 Ser-473 phosphorylation increased E2F1-targeted proapoptotic gene expression and E2F1-induced apoptosis in response to DNA damage. Furthermore, loss of phosphorylation of KAP1 Ser-473 led to less BRCA1 focus formation and slower kinetics of loss of gamma H2AX foci after DNA damage. KAP1 Ser-473 phosphorylation was required for efficient DNA repair and cell survival in response to DNA damage. Our studies reveal novel functions of KAP1 Ser-473 phosphorylation under stress.