Nucleotide Excision Repair, XPA-1, and the Translesion Synthesis Complex, POLZ-1 and REV-1, Are Critical for Interstrand Cross-Link Repair in Caenorhabditis elegans Germ Cells.
Nucleotide Excision Repair, XPA-1, and the Translesion Synthesis Complex, POLZ-1 and REV-1, Are Critical for Interstrand Cross-Link Repair in Caenorhabditis elegans Germ Cells.
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核苷酸切除修复，XPA-1和Translesion合成复合物POLZ-1和REV-1对于秀丽隐杆线虫生殖细胞中链间交联修复至关重要。
DOI：
10.1021/acs.biochem.0c00719
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发表时间：
2020-09-29
期刊：
影响因子：
2.9
通讯作者：
Lee MH
中科院分区：
文献类型：
--
作者：
Oh S;Bae W;Alfhili MA;Lee MH
链间交联(ICL)是在相反的DNA链上共价连接的核苷酸的加合物，阻止复制和启动细胞恶性转化或细胞过早死亡。ICL可能是由烷化剂或紫外线(UV)照射引起的。这些毒性损伤可通过不同的修复机制去除，如Fanconi贫血(FA)途径、核苷酸切除修复(NER)、跨损伤合成(TLS)和同源重组(HR)。在哺乳动物中，着色性干皮病F组(XP-F)蛋白参与FA途径和NER途径，而ζ聚合酶(PolZ-1)和REV-1介导TLS。然而，关于生殖细胞ICL修复和损伤耐受中这些通路的遗传决定因素知之甚少。在这项研究中，我们检测了线虫生殖细胞对三甲基补骨脂素/紫外线A(TMP/UV-A)联合产生的ICL的敏感性，并以胚胎死亡率作为生殖细胞DNA损伤的替代指标。我们的结果表明，在线虫生殖细胞中，XPA-1、POLZ-1和REV-1比FA途径介体在维持基因组稳定性方面更关键。值得注意的是，缺乏XPA-1和Polz-1(或REV-1)的突变虫比单独缺乏任何一个突变的虫子对ICLS更敏感。此外，XPA-1和Rev-1的敲除导致RPA-1和RAD-51在ICL损伤时焦点的延迟消失。由于DNA修复机制是广泛保守的，我们的发现可能会对人类未来的治疗干预产生影响。
Interstrand crosslinks (ICLs) are adducts of covalently linked nucleotides in opposing DNA strands that obstruct replication and prime cells for malignant transformation or premature cell death. ICLs may be caused by alkylating agents or ultraviolet (UV) irradiation. These toxic lesions are removed by diverse repair mechanisms such as Fanconi anemia (FA) pathway, nucleotide excision repair (NER), translesion synthesis (TLS), and homologous recombination (HR). In mammals, xeroderma pigmentosum group F (XP-F) protein participates in both FA pathway and NER, while DNA polymerase ζ (POLZ-1) and REV-1 mediate TLS. Nevertheless, little is known regarding the genetic determinants of these pathways in ICL repair and damage tolerance in germ cells. In this study, we examined the sensitivity of C. elegans germ cells to ICLs generated by trimethylpsoralen/ultraviolet A (TMP/UV-A) combination, and embryonic mortality was employed as a surrogate for DNA damage in germ cells. Our results show that XPA-1, POLZ-1, and REV-1 were more critical than FA pathway mediators in preserving genomic stability in C. elegans germ cells. Notably, mutant worms lacking both XPA-1 and POLZ-1 (or REV-1) were more sensitive to ICLs compared to either single mutant alone. Moreover, knockdown of XPA-1 and REV-1 leads to retarded disappearance of RPA-1 and RAD-51 foci upon ICL damage. Since DNA repair mechanisms are broadly conserved, our findings may have ramifications for prospective therapeutic interventions in humans.
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DOI：
10.1186/s41021-016-0037-9
发表时间：
2016
期刊：
Genes and environment : the official journal of the Japanese Environmental Mutagen Society
影响因子：
--
作者：
Hashimoto S;Anai H;Hanada K
通讯作者：
Hanada K
影响因子：
4.5
作者：
Agostinho A;Meier B;Sonneville R;Jagut M;Woglar A;Blow J;Jantsch V;Gartner A
通讯作者：
Gartner A
影响因子：
5.6
作者：
Mccabe, Kevin M.;Olson, Susan B.;Moses, Robb E.
通讯作者：
Moses, Robb E.
影响因子：
4.2
作者：
Feng WH;Xue KS;Tang L;Williams PL;Wang JS
通讯作者：
Wang JS
影响因子：
3.8
作者：
Jansen, Jacob G.;Tsaalbi-Shtylik, Anastasia;de Wind, Niels
通讯作者：
de Wind, Niels