A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G: implications for a second XPG function.
A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G: implications for a second XPG function.
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DOI：
10.1073/pnas.94.7.3116
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发表时间：
1997-04
影响因子：
11.1
通讯作者：
T. Nouspikel;P. Lalle;S. Leadon;P. Cooper;S. Clarkson
中科院分区：
文献类型：
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作者：
T. Nouspikel;P. Lalle;S. Leadon;P. Cooper;S. Clarkson
着色性干皮病 (XP) 患者的核苷酸切除修复 (NER) 存在缺陷，NER 是一种多功能修复途径，可消除紫外线引起的损伤和其他庞大的 DNA 加合物。科凯恩综合征 (CS) 是另一种罕见的阳光敏感性疾病，患者在优先去除活性基因转录链的损伤方面存在特别缺陷，这一过程称为转录偶联修复。这两种疾病通常在临床和遗传上是不同的，但互补分析已将一些 CS 患者分配到罕见的 XP 组 B、D 或 G。 XPG 基因编码一种结构特异性核酸内切酶，该酶在 NER 过程中将损伤的 DNA 3' 切开。在这里，我们展示了三名 XPG/CS 患者的突变，这些突变会产生严重截短的 XPG 蛋白。相比之下，两个没有 CS 的同胞 XPG 患者能够产生全长 XPG，但具有错义突变，使其在 NER 中的功能失活。这些结果表明 XPG/CS 突变消除了第二个重要 XPG 功能所需的相互作用，并且正是第二个功能的丧失导致了 CS 临床表型。
Xeroderma pigmentosum (XP) patients have defects in nucleotide excision repair (NER), the versatile repair pathway that removes UV-induced damage and other bulky DNA adducts. Patients with Cockayne syndrome (CS), another rare sun-sensitive disorder, are specifically defective in the preferential removal of damage from the transcribed strand of active genes, a process known as transcription-coupled repair. These two disorders are usually clinically and genetically distinct, but complementation analyses have assigned a few CS patients to the rare XP groups B, D, or G. The XPG gene encodes a structure-specific endonuclease that nicks damaged DNA 3' to the lesion during NER. Here we show that three XPG/CS patients had mutations that would produce severely truncated XPG proteins. In contrast, two sibling XPG patients without CS are able to make full-length XPG, but with a missense mutation that inactivates its function in NER. These results suggest that XPG/CS mutations abolish interactions required for a second important XPG function and that it is the loss of this second function that leads to the CS clinical phenotype.