Functional regulation of the DNA damage-recognition factor DDB2 by ubiquitination and interaction with xeroderma pigmentosum group C protein.
Functional regulation of the DNA damage-recognition factor DDB2 by ubiquitination and interaction with xeroderma pigmentosum group C protein.
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DOI：
10.1093/nar/gkv038
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发表时间：
2015-02-18
影响因子：
14.9
通讯作者：
Sugasawa K
中科院分区：
文献类型：
--
作者：
Matsumoto S;Fischer ES;Yasuda T;Dohmae N;Iwai S;Mori T;Nishi R;Yoshino K;Sakai W;Hanaoka F;Thomä NH;Sugasawa K
在哺乳动物核苷酸切除修复中，DDB 1-DDB 2复合物识别UV诱导的DNA光损伤并促进XPC复合物的募集。在与受损DNA结合后，与DDB 1-DDB 2相关的Cullin 4泛素连接酶被激活并泛素化DDB 2和XPC。DDB 2的结构紊乱的N-末端尾含有7个赖氨酸，被鉴定为泛素化的主要位点，靶向蛋白质进行蛋白酶体降解;然而，这些修饰的精确生物学功能仍然未知。通过在正常人成纤维细胞中外源性表达突变DDB 2蛋白，我们发现DDB 2的N-末端尾参与调节细胞对UV的反应。通过与外源DDB 2的行为形成鲜明对比，内源DDB 2蛋白即使在UV照射后也是稳定的，作为XPC表达水平的函数。此外，XPC在体外竞争性抑制DDB 2的泛素化，这种作用被centrin-2显著促进，其增强了XPC的DNA损伤识别活性。基于这些发现，我们提出，在暴露于紫外线的细胞中，DDB 2被XPC以随机方式保护免于泛素化和降解;因此XPC允许DDB 2启动多轮修复事件，从而有助于细胞DNA修复能力的持久性。
In mammalian nucleotide excision repair, the DDB1–DDB2 complex recognizes UV-induced DNA photolesions and facilitates recruitment of the XPC complex. Upon binding to damaged DNA, the Cullin 4 ubiquitin ligase associated with DDB1–DDB2 is activated and ubiquitinates DDB2 and XPC. The structurally disordered N-terminal tail of DDB2 contains seven lysines identified as major sites for ubiquitination that target the protein for proteasomal degradation; however, the precise biological functions of these modifications remained unknown. By exogenous expression of mutant DDB2 proteins in normal human fibroblasts, here we show that the N-terminal tail of DDB2 is involved in regulation of cellular responses to UV. By striking contrast with behaviors of exogenous DDB2, the endogenous DDB2 protein was stabilized even after UV irradiation as a function of the XPC expression level. Furthermore, XPC competitively suppressed ubiquitination of DDB2 in vitro, and this effect was significantly promoted by centrin-2, which augments the DNA damage-recognition activity of XPC. Based on these findings, we propose that in cells exposed to UV, DDB2 is protected by XPC from ubiquitination and degradation in a stochastic manner; thus XPC allows DDB2 to initiate multiple rounds of repair events, thereby contributing to the persistence of cellular DNA repair capacity.
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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：
16.8
作者：
Camenisch, U;Dip, R;Naegeli, H
通讯作者：
Naegeli, H
影响因子：
4.8
作者：
Araki, M;Masutani, C;Hanaoka, F
通讯作者：
Hanaoka, F
影响因子：
3.6
作者：
Amundson, SA;Patterson, A;Fornace, AJ
通讯作者：
Fornace, AJ
DOI：
10.1073/pnas.0511160103
发表时间：
2006-02-21
影响因子：
11.1
作者：
Kapetanaki, MG;Guerrero-Santoro, J;Levine, AS
通讯作者：
Levine, AS