Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection.
Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection.
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DOI：
10.1038/ncomms12628
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发表时间：
2016-08-26
影响因子：
16.6
通讯作者：
Sartori, Alessandro A.
中科院分区：
文献类型：
--
作者：
Ferretti, Lorenza P.;Himmels, Sarah-Felicitas;Trenner, Anika;Walker, Christina;von Aesch, Christine;Eggenschwiler, Aline;Murina, Olga;Enchev, Radoslav I.;Peter, Matthias;Freire, Raimundo;Porro, Antonio;Sartori, Alessandro A.
人CtIP是DNA双链断裂修复途径选择中的决定性因素，通过使DNA末端切除成为可能，这是区分同源重组（HR）与非同源末端连接（NHEJ）的第一步。为了协调DNA末端切除的适当和及时执行，CtIP功能受到多种蛋白质-蛋白质相互作用和翻译后修饰的严格控制。在这里，我们确定了Cullin 3 E3连接酶底物接头Kelch样蛋白15（KLHL 15）作为CtIP的一个新的相互作用伙伴，并表明KLHL 15通过泛素-蛋白酶体途径促进CtIP蛋白的周转。在脊椎动物CtIP蛋白中保守的三肽基序（FRY）对于KLHL 15结合是必不可少的;其突变阻断KLHL 15依赖性CtIP泛素化和降解。因此，DNA末端切除在过表达KLHL 15的细胞中强烈减弱，但在表达CtIP-FRY突变体或缺乏KLHL 15的细胞中扩增，从而影响HR和NHEJ之间的平衡。总的来说，我们的研究结果强调了CtIP调节基因组完整性的关键重要性和高度复杂性。 CtIP在DNA双链断裂修复中具有关键作用，因为其在断裂处切除DNA的作用使细胞进行同源重组。在这里，作者表明KLHL 15与CtIP相互作用，并通过控制蛋白质周转来调节修复。
Human CtIP is a decisive factor in DNA double-strand break repair pathway choice by enabling DNA-end resection, the first step that differentiates homologous recombination (HR) from non-homologous end-joining (NHEJ). To coordinate appropriate and timely execution of DNA-end resection, CtIP function is tightly controlled by multiple protein–protein interactions and post-translational modifications. Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway. A tripeptide motif (FRY) conserved across vertebrate CtIP proteins is essential for KLHL15-binding; its mutation blocks KLHL15-dependent CtIP ubiquitination and degradation. Consequently, DNA-end resection is strongly attenuated in cells overexpressing KLHL15 but amplified in cells either expressing a CtIP-FRY mutant or lacking KLHL15, thus impacting the balance between HR and NHEJ. Collectively, our findings underline the key importance and high complexity of CtIP modulation for genome integrity. CtIP has a key role in DNA double-strand break repair as its role in resecting DNA at the break commits a cell to homologous recombination. Here the authors show that KLHL15 interacts with CtIP and regulates repair by controlling protein turnover.
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影响因子：
16.8
作者：
Andres, Sara N.;Appel, C. Denise;Westmoreland, James W.;Williams, Jessica S.;Nguyen, Yvonne;Robertson, Patrick D.;Resnick, Michael A.;Williams, R. Scott
通讯作者：
Williams, R. Scott
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：
14.8
作者：
Forment JV;Jackson SP
通讯作者：
Jackson SP
影响因子：
64.5
作者：
Duda, David M.;Borg, Laura A.;Scott, Daniel C.;Hunt, Harold W.;Hammel, Michal;Schulman, Brenda A.
通讯作者：
Schulman, Brenda A.
影响因子：
4
作者：
Chapman, J. Ross;Sossick, Alex J.;Jackson, Stephen P.
通讯作者：
Jackson, Stephen P.