NBS1 I171V variant underlies individual differences in chromosomal radiosensitivity within human populations.
NBS1 I171V variant underlies individual differences in chromosomal radiosensitivity within human populations.
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DOI：
10.1038/s41598-021-98673-7
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发表时间：
2021-10-04
影响因子：
4.6
通讯作者：
Matsuura S
中科院分区：
文献类型：
--
作者：
Tomioka K;Miyamoto T;Akutsu SN;Yanagihara H;Fujita K;Royba E;Tauchi H;Yamamoto T;Koh I;Hirata E;Kudo Y;Kobayashi M;Okada S;Matsuura S
通过DNA双链断裂（DSB）修复机制，遗传信息可免受各种遗传毒素（包括电离辐射（IR））的影响。全基因组关联研究和癌症患者的临床测序表明，DNA DSB修复基因中的许多变体可能是人群中染色体放射敏感性个体差异的基础。然而，直接影响放射敏感性的已确定变异的数量仍然有限。在这项研究中，我们对29名日本卵巢癌患者进行了全外显子组测序，并在一名患者中检测到了NBS 1 I171 V变异体，据估计，该变异体在健康人群中的存在率约为0.15%。为了阐明该变体是否确实有助于染色体放射敏感性，我们使用CRISPR/Cas9系统产生了NBS 1 I171 V变体纯合敲入HCT 116细胞和小鼠。辐射诱导的微核形成和染色体畸变频率显着增加，在HCT 116细胞和小鼠胚胎成纤维细胞（MEFs）与NBS 1 I171 V变体的敲入水平相比，在野生型细胞。这些结果表明，NBS 1 I171 V变异可能是一个遗传因素的染色体辐射敏感性的个体差异。
Genetic information is protected against a variety of genotoxins including ionizing radiation (IR) through the DNA double-strand break (DSB) repair machinery. Genome-wide association studies and clinical sequencing of cancer patients have suggested that a number of variants in the DNA DSB repair genes might underlie individual differences in chromosomal radiosensitivity within human populations. However, the number of established variants that directly affect radiosensitivity is still limited. In this study, we performed whole-exome sequencing of 29 Japanese ovarian cancer patients and detected the NBS1 I171V variant, which is estimated to exist at a rate of approximately 0.15% in healthy human populations, in one patient. To clarify whether this variant indeed contributes to chromosomal radiosensitivity, we generated NBS1 I171V variant homozygous knock-in HCT116 cells and mice using the CRISPR/Cas9 system. Radiation-induced micronucleus formation and chromosomal aberration frequency were significantly increased in both HCT116 cells and mouse embryonic fibroblasts (MEFs) with knock-in of the NBS1 I171V variant compared with the levels in wild-type cells. These results suggested that the NBS1 I171V variant might be a genetic factor underlying individual differences in chromosomal radiosensitivity.
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DOI：
10.1016/j.mrrev.2020.108342
发表时间：
2020-10-01
影响因子：
5.3
作者：
Fenech, Michael;Knasmueller, Siegfried;Kirsch-Volders, Micheline
通讯作者：
Kirsch-Volders, Micheline
影响因子：
4.6
作者：
Rusak, Bogna;Kluzniak, Wojciech;Sasiadek, Maria Malgorzata
通讯作者：
Sasiadek, Maria Malgorzata
影响因子：
2
作者：
Komatsu K
通讯作者：
Komatsu K
DOI：
10.1126/science.abb1390
发表时间：
2020-07-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lapinaite A;Knott GJ;Palumbo CM;Lin-Shiao E;Richter MF;Zhao KT;Beal PA;Liu DR;Doudna JA
通讯作者：
Doudna JA
影响因子：
64.8
作者：
Anzalone, Andrew V.;Randolph, Peyton B.;Liu, David R.
通讯作者：
Liu, David R.