Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans.
Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans.
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发表时间：
1998-02
期刊：
影响因子：
11.2
通讯作者：
Shen Mr;Jones Im;H. Mohrenweiser
中科院分区：
文献类型：
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作者：
Shen Mr;Jones Im;H. Mohrenweiser
DNA损伤的去除或修复在保护细胞基因组免受致癌物质的侵害方面具有关键作用。这最初在患有罕见遗传疾病着色性干皮病（癌症基因的范例）的个体中得到证实，随后在错配修复与结肠癌之间的关系中得到证实。最近的报告表明，在人群中观察到多态性频率的个体修复DNA损伤的能力降低幅度较小;这些个体对乳腺癌、肺癌和皮肤癌的易感性增加。我们报告了一项研究的初步结果，以估计DNA修复途径的蛋白质编码基因中个体之间DNA序列变异的程度。在对三个核苷酸切除修复基因（ERCC 1、XPD和XPF）、一个参与双链断裂修复/重组基因（XRCC 3）和一个在碱基切除修复和辐射诱导损伤修复中起作用的基因（XRCCI）的外显子进行重测序中，已经鉴定出九种不同的氨基酸取代变体。在一组12名健康个体中，9种不同变异等位基因的频率范围为0.04至0.45;平均等位基因频率为0.17。这种变异，特别是在人类和小鼠中相同的残基处发生的六个非保守氨基酸取代，可能导致DNA修复能力或DNA修复保真度降低的可能性是有趣的;变异体作为癌症风险因素或易感性等位基因的作用仍有待解决。
The removal or repair of DNA damage has a key role in protecting the genome of the cell from the insults of cancer-causing agents. This was originally demonstrated in individuals with the rare genetic disease xeroderma pigmentosum, the paradigm of cancer genes, and subsequently in the relationship between mismatch repair and colon cancer. Recent reports suggest that individuals with less dramatic reductions in the capacity to repair DNA damage are observed at polymorphic frequency in the population; these individuals have an increased susceptibility to breast, lung, and skin cancer. We report initial results from a study to estimate the extent of DNA sequence variation among individuals in genes encoding proteins of the DNA repair pathways. Nine different amino acid substitution variants have been identified in resequencing of the exons of three nucleotide excision repair genes (ERCC1, XPD, and XPF), a gene involved in double-strand break repair/recombination genes (XRCC3), and a gene functioning in base excision repair and the repair of radiation-induced damage (XRCCI). The frequencies for the nine different variant alleles range from 0.04 to 0.45 in a group of 12 healthy individuals; the average allele frequency is 0.17. The potential that this variation, and especially the six nonconservative amino acid substitutions occurring at residues that are identical in human and mouse, may cause reductions in DNA repair capacity or the fidelity of DNA repair is intriguing; the role of the variants as cancer risk factors or susceptibility alleles remains to be addressed.