NUCLEOTIDE EXCISION-REPAIR SYNDROMES - MOLECULAR-BASIS AND CLINICAL SYMPTOMS
NUCLEOTIDE EXCISION-REPAIR SYNDROMES - MOLECULAR-BASIS AND CLINICAL SYMPTOMS
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DOI：
10.1098/rstb.1995.0012
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发表时间：
1995-01-30
期刊：
影响因子：
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通讯作者：
HOEIJMAKERS, J
中科院分区：
文献类型：
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作者：
BOOTSMA, D;WEEDA, G;HOEIJMAKERS, J
人类核苷酸切除修复（NER）缺陷的表型后果明显表现为三种不同的先天性疾病，其特征是皮肤对紫外线过敏，并且具有显著的临床和遗传异质性。这些是原型修复综合征，色素性干皮病（XP）（七个基因互补组，指定为XP- a到XP- g）， Cockayne综合征（两组：CS-A和CS-B）和PIBIDS，一种特殊的光敏形式的脆性毛发疾病毛磷营养不良（TTD，至少两组，其中一组相当于XP- d）。为了研究NER的发生机制和解决这些NER缺乏性疾病的分子缺陷，我们重点研究了人类DNA修复基因的克隆和鉴定。我们克隆的基因之一是ERCC3。它指定了一个染色质结合解旋酶。转染和显微注射实验表明，ERCC3突变负责XP补体B组，这是一种非常罕见的XP形式，同时与科克凯恩综合征（CS）相关。ERCC3蛋白被发现是大多数结构基因转录起始和NER所需的多蛋白复合物（TFIIH）的一部分。这就定义了基因的另一个迄今未知的重要功能。我们将讨论ERCC3基因和其他几个参与转录起始的NER基因。
The phenotypic consequences of a nucleotide excision repair (NER) defect in man are apparent from three distinct inborn diseases characterized by hypersensitivity of the skin to ultraviolet light and a remarkable clinical and genetic heterogeneity. These are the prototype repair syndrome, xeroderma pigmentosum (XP) (seven genetic complementation groups, designated XP-A to XP-G), Cockayne's syndrome (two groups: CS-A and CS-B) and PIBIDS, a peculiar photosensitive form of the brittle hair disease trichothiodystrophy (TTD, at least two groups of which one equivalent to XP-D).To investigate the mechanism of NER and to resolve the molecular defect in these NER deficiency diseases we have focused on the cloning and characterization of human DNA repair genes. One of the genes that we cloned is ERCC3. It specifies a chromatin binding helicase. Transfection and microinjection experiments demonstrated that mutations in ERCC3 are responsible for XP complementation group B, a very rare form of XP that is simultaneously associated with Cockayne's syndrome (CS). The ERCC3 protein was found to be part of a multiprotein complex (TFIIH) required for transcription initiation of most structural genes and for NER. This defines the additional, hitherto unknown vital function of the gene. This ERCC3 gene and several other NER genes involved in transcription initiation will be discussed.