WASH interacts with Ku to regulate DNA double-stranded break repair.
WASH interacts with Ku to regulate DNA double-stranded break repair.
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WASH与Ku相互作用调节DNA双链断裂修复
DOI：
10.1016/j.isci.2021.103676
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发表时间：
2022-01-21
期刊：
影响因子：
5.8
通讯作者：
Deng ZH
中科院分区：
文献类型：
--
作者：
Wang T;Du XH;Hong Y;Hong X;Fan L;Zhou JW;Sun H;Ge J;Billadeau DD;Deng ZH
Wiskott-Aldrich综合征蛋白和SCAR同系物（WASH）是一种肌动蛋白成核促进因子，存在于细胞核中，在那里它调节基因转录并维持核组织。在这里，我们表明，WASH与核心非同源末端连接（NHEJ）因子，包括Ku 70/Ku 80和DNA-PKcs相互作用，Ku 70/Ku 80参与WASH的招募到DNA双链断裂（DSB）的网站。WASH消耗导致细胞敏感性增加，DNA修复能力受损，以响应依托泊苷诱导的DSB，并降低NHEJ效率。从机制上讲，我们发现WASH的丢失抑制了DSB诱导后DNA-PKcs，H2 AX和KAP 1的磷酸化，并减少了染色质松弛和几种下游NHEJ因子向DSB的募集。此外，WASH在DSB修复中的作用取决于其保守的C-末端VCA结构域和Arp 2/3激活。我们的研究结果揭示了WASH通过NHEJ途径在DNA DSB修复中的功能和机制见解。WASH通过与Ku相互作用定位于DSB位点WASH通过NHEJ途径促进DNA修复WASH通过H2 AX和KAP 1的磷酸化促进染色质松弛VCA结构域对WASH依赖性DSB修复至关重要生物科学;分子生物学;细胞生物学
The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH), an actin nucleation-promoting factor, is present in the nucleus where it regulates gene transcription and maintains nuclear organization. Here, we show that WASH interacts with core non-homologous end-joining (NHEJ) factors including Ku70/Ku80 and DNA-PKcs, and Ku70/Ku80 is involved in the recruitment of WASH to the sites of DNA double-stranded break (DSB). WASH depletion leads to increased cell sensitivity and impaired DNA repair capacity in response to etoposide-induced DSBs and reduces NHEJ efficiency. Mechanistically, we show that loss of WASH inhibits the phosphorylation of DNA-PKcs, H2AX, and KAP1 after DSB induction and reduces chromatin relaxation and the recruitment of several downstream NHEJ factors to DSBs. Moreover, WASH role in DSB repair depends on its conserved C-terminal VCA domain and Arp2/3 activation. Our findings reveal a function and mechanistic insight for WASH in DNA DSB repair by the NHEJ pathway. WASH localizes to DSB sites by interacting with Ku WASH promotes DNA repair though NHEJ pathway WASH promotes chromatin relaxation through phosphorylation of H2AX and KAP1 VCA domain is essential for WASH-dependent DSB repair Biological sciences; Molecular biology; Cell biology
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
4.8
作者：
Calsou, P;Frit, P;Salles, B
通讯作者：
Salles, B
影响因子：
16.8
作者：
Kapoor, Prabodh;Chen, Mingming;Winkler, Duane David;Luger, Karolin;Shen, Xuetong
通讯作者：
Shen, Xuetong
影响因子：
19
作者：
Kapoor, Prabodh;Shen, Xuetong
通讯作者：
Shen, Xuetong
影响因子：
14.9
作者：
Kienker, LJ;Shin, EK;Meek, K
通讯作者：
Meek, K