Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair
Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair
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DOI：
10.1038/ng.2228
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发表时间：
2012-05-01
期刊：
影响因子：
30.8
通讯作者：
Tanaka, Kiyoji
中科院分区：
文献类型：
--
作者：
Zhang, Xue;Horibata, Katsuyoshi;Tanaka, Kiyoji
紫外线敏感综合征（（UVS）-S-S）是一种常染色体隐性遗传疾病，其特征为光敏性和转录偶联修复（TCR）缺陷，TCR是核苷酸切除修复的一种子途径，可快速消除转录阻断DNA损伤（1）。Cockayne综合征是一种TCR缺陷相关疾病，由两个互补组Cockayne综合征（CS）-A和CS-B组成，分别由ERCC 8（CSA）和ERCC 6（CSB）突变引起（2）。（UVS）-S-S包括三个组，（UVS）-S-S/CS-A、（UVS）-S-S/CS-B和（UVS）-S-S-A，分别由ERCC 8、ERCC 6和未鉴定的基因中的突变引起（3-6）。本文报道了利用微细胞介导的染色体转移技术克隆（UVS）-S-S-A突变基因。预测的人类基因UVSSA（以前称为KIAA 1530）（7）校正（UVS）-S-S-A细胞中的缺陷TCR。我们在（UVS）-S-S-A患者中发现了三个无义和移码的UVSSA突变，表明UVSSA是该综合征的致病基因。UVSSA蛋白与USP 7形成复合物（参考文献8），稳定ERCC 6并在UV照射后恢复RNA聚合酶II的低磷酸化形式。
UV-sensitive syndrome ((UVS)-S-S) is an autosomal recessive disorder characterized by photosensitivity and deficiency in transcription-coupled repair (TCR), a subpathway of nucleotide-excision repair that rapidly removes transcription-blocking DNA damage(1). Cockayne syndrome is a related disorder with defective TCR and consists of two complementation groups, Cockayne syndrome (CS)-A and CS-B, which are caused by mutations in ERCC8 (CSA) and ERCC6 (CSB), respectively(2). (UVS)-S-S comprises three groups, (UVS)-S-S/CS-A, (UVS)-S-S/CS-B and (UVS)-S-S-A, caused by mutations in ERCC8, ERCC6 and an unidentified gene, respectively(3-6). Here, we report the cloning of the gene mutated in (UVS)-S-S-A by microcell-mediated chromosome transfer. The predicted human gene UVSSA (formerly known as KIAA1530)(7) corrects defective TCR in (UVS)-S-S-A cells. We identify three nonsense and frameshift UVSSA mutations in individuals with (UVS)-S-S-A, indicating that UVSSA is the causative gene for this syndrome. The UVSSA protein forms a complex with USP7 (ref. 8), stabilizes ERCC6 and restores the hypophosphorylated form of RNA polymerase II after UV irradiation.