Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks.
Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks.
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DNA双链断裂（DSB）是由电离辐射（IR）和各种DNA损伤化学物质产生的高度细胞毒性损伤。在DSB形成后，细胞激活DNA损伤反应（DDR）蛋白激酶ATM、ATR和DNA-PK。然后，这些触发组蛋白H2 AX磷酸化和蛋白质如MDC 1、53 BP 1、BRCA 1、CtIP、RNF 8和RNF 168/RIDDLIN积累到IR诱导的病灶（IRIF）中，其放大DSB信号传导并促进DSB修复。小泛素相关修饰物（SUMO）与靶蛋白的连接控制着多种细胞功能。在这里，我们发现SUMO 1，SUMO 2和SUMO 3积累在哺乳动物细胞的DSB位点，SUMO 1和SUMO 2/3的积累需要E3连接酶PIAS 4和PIAS 1。我们还确定PIAS 1和PIAS 4通过需要其SAP结构域的机制被招募到损伤位点，并且是53 BP 1，BRCA 1和RNF 168与这些区域的生产性关联所必需的。此外，我们发现PIAS 1和PIAS 4促进DSB修复并赋予IR抗性。最后，我们确定PIAS 1和PIAS 4是在DNA损伤位点由RNF 8、RNF 168和BRCA 1介导的有效泛素加合物形成所必需的。因此，这些研究结果确定PIAS 1和PIAS 4作为DDR的组成部分，并揭示了蛋白质募集到DSB位点是如何通过协调的sumoylation和ubiquitylation来控制的。
DNA double-strand breaks (DSBs) are highly cytotoxic lesions that are generated by ionizing radiation (IR) and various DNA-damaging chemicals. Following DSB formation, cells activate the DNA-damage response (DDR) protein kinases ATM, ATR and DNA-PK. These then trigger histone H2AX phosphorylation and the accumulation of proteins such as MDC1, 53BP1, BRCA1, CtIP, RNF8 and RNF168/RIDDLIN into IR-induced foci (IRIF) that amplify DSB signalling and promote DSB repair. Attachment of Small Ubiquitin-related modifier (SUMO) to target proteins controls diverse cellular functions. Here, we show that SUMO1, SUMO2 and SUMO3 accumulate at DSB sites in mammalian cells, with SUMO1 and SUMO2/3 accrual requiring the E3 ligase enzymes PIAS4 and PIAS1. We also establish that PIAS1 and PIAS4 are recruited to damage sites via mechanisms requiring their SAP domains, and are needed for the productive association of 53BP1, BRCA1 and RNF168 with such regions. Furthermore, we show that PIAS1 and PIAS4 promote DSB repair and confer IR resistance. Finally, we establish that PIAS1 and PIAS4 are required for effective Ubiquitin-adduct formation mediated by RNF8, RNF168 and BRCA1 at sites of DNA damage. These findings thus identify PIAS1 and PIAS4 as components of the DDR and reveal how protein recruitment to DSB sites is controlled by coordinated sumoylation and ubiquitylation.
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影响因子：
16
作者：
Lou, ZK;Minter-Dykhouse, K;Chen, JJ
通讯作者：
Chen, JJ
影响因子：
64.8
作者：
Stewart, GS;Wang, B;Elledge, SJ
通讯作者：
Elledge, SJ
影响因子：
4
作者：
Evdokimov, Evgenij;Sharma, Prashant;Kuehn, Michael R.
通讯作者：
Kuehn, Michael R.
影响因子：
10.5
作者：
Pierce, AJ;Hu, P;Jasin, M
通讯作者：
Jasin, M
DOI：
10.1073/pnas.0701877104
发表时间：
2007-07-10
影响因子：
11.1
作者：
Tahk, Samuel;Liu, Bin;Shuai, Ke
通讯作者：
Shuai, Ke