K63-linked polyubiquitin chains bind to DNA to facilitate DNA damage repair.
K63-linked polyubiquitin chains bind to DNA to facilitate DNA damage repair.
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DOI：
10.1126/scisignal.aar8133
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发表时间：
2018-06-05
影响因子：
7.3
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Liu P;Gan W;Su S;Hauenstein AV;Fu TM;Brasher B;Schwerdtfeger C;Liang AC;Xu M;Wei W
多泛素化通常被视为控制蛋白质稳定性或蛋白质-蛋白质相互作用的翻译后修饰，其中不同的多泛素连接最终决定修饰蛋白质的命运(S)。我们探索了多泛素链是否具有任何非蛋白质相关的功能。使用体外合成材料的下拉实验，我们发现带有Lys63(K63)连接的多泛素链通过一个我们称为“DNA相互作用补丁”(DIP)的基序与DNA结合，该基序由邻近的残基Thr9、Lys11和Glu34组成。在DNA损伤时，K63连接的多泛素链与DNA的结合通过它们与泛素中的Ile44补丁的相互作用促进了修复因子的招募，从而促进了DNA修复。此外，DIP内的实验性或癌症患者来源的突变削弱了泛素的DNA结合能力，随后减弱了K63连接的多泛素链在DNA损伤部位的积累，从而导致DNA修复缺陷，并增加了细胞对DNA损伤剂的敏感性。因此，我们的结果强调了K63连接的多泛素链在与DNA结合以促进DNA损伤修复中的关键生理作用。
Polyubiquitylation is canonically viewed as a posttranslational modification that governs protein stability or protein-protein interactions, in which distinct polyubiquitin linkages ultimately determine the fate of modified protein(s). We explored whether polyubiquitin chains have any nonprotein-related function. Using in vitro pull-down assays with synthetic materials, we found that polyubiquitin chains with the Lys63 (K63) linkage bound to DNA through a motif we called the “DNA-interacting patch” (DIP), which is composed of the adjacent residues Thr9, Lys11, and Glu34. Upon DNA damage, the binding of K63-linked polyubiquitin chains to DNA enhanced the recruitment of repair factors through their interaction with an Ile44 patch in ubiquitin to facilitate DNA repair. Furthermore, experimental or cancer patient–derived mutations within the DIP impaired the DNA binding capacity of ubiquitin and subsequently attenuated K63-linked polyubiquitin chain accumulation at sites of DNA damage, thereby resulting in defective DNA repair and increased cellular sensitivity to DNA-damaging agents. Our results therefore highlight a critical physiological role for K63-linked polyubiquitin chains in binding to DNA to facilitate DNA damage repair.
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影响因子：
16
作者：
Liu, Pengda;Gan, Wenjian;Guo, Chunguang;Xie, Anyong;Gao, Daming;Guo, Jianping;Zhang, Jinfang;Willis, Nicholas;Su, Arthur;Asara, John M.;Scully, Ralph;Wei, Wenyi
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Wei, Wenyi
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Elledge SJ
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--
影响因子：
64.5
作者：
Deng, L;Wang, C;Chen, ZJ
通讯作者：
Chen, ZJ