Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair
Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair
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DOI：
10.1038/ng.2229
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发表时间：
2012-05-01
期刊：
影响因子：
30.8
通讯作者：
Ogi, Tomoo
中科院分区：
文献类型：
--
作者：
Nakazawa, Yuka;Sasaki, Kensaku;Ogi, Tomoo
紫外线敏感综合征（（UVS）-S-S）是一种遗传性皮肤病，其特征为皮肤光敏性，但不伴皮肤癌（1-4）。尽管有轻微的临床特征，但来自（UVS）-S-S个体的细胞，如Cockayne综合征细胞，对紫外线非常敏感，并且缺乏转录偶联核苷酸切除修复（TC-NER）（2，4，5），该修复可消除活跃转录基因中的DNA损伤（6）。七个已知的（UVS）-S-S病例中的三个携带Cockayne综合征基因ERCC 8或ERCC 6（也分别称为CSA和CSB）的突变（7，8）。剩下的4个携带（UVS）-S-S的个体，其中一个在这里首次描述，形成了一个单独的（UVS）-S-S-A互补组（1，9，10）;然而，负责的基因是未知的。使用外显子组测序（11），我们确定UVSSA基因（以前称为KIAA 1530）的突变导致（UVS）-S-S-A。UVSSA蛋白与TC-NER机制相互作用并稳定ERCC 6复合物;它还促进停滞在DNA损伤位点的RNA聚合酶IIo的泛素化。我们的研究结果为停滞的RNA聚合酶的加工提供了机制上的见解，并解释了这些TC-NER缺陷性疾病的不同临床特征。
UV-sensitive syndrome ((UVS)-S-S) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma(1-4). Despite mild clinical features, cells from individuals with (UVS)-S-S, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER)(2,4,5), which removes DNA damage in actively transcribed genes(6). Three of the seven known (UVS)-S-S cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively)(7,8). The remaining four individuals with (UVS)-S-S, one of whom is described for the first time here, formed a separate (UVS)-S-S-A complementation group(1,9,10); however, the responsible gene was unknown. Using exome sequencing(11), we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause (UVS)-S-S-A. The UVSSA protein interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites. Our findings provide mechanistic insights into the processing of stalled RNA polymerase and explain the different clinical features across these TC-NER-deficient disorders.