Tsaalbi-Shtylik Anastasia, Ferrás Cristina, Pauw Bea, Hendriks Giel, Temviriyanukul Piya, Carlée Leone, Calléja Fabienne, van Hees Sandrine, Akagi Jun-Ichi, Iwai Shigenori, Hanaoka Fumio, Jansen Jacob G, de Wind Niels
Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
Faculty of Science, Gakushuin University, Tokyo 171-0031, Japan.
J Cell Biol. 2015 Apr 13;209(1):33-46. doi: 10.1083/jcb.201408017.
In addition to correcting mispaired nucleotides, DNA mismatch repair (MMR) proteins have been implicated in mutagenic, cell cycle, and apoptotic responses to agents that induce structurally aberrant nucleotide lesions. Here, we investigated the mechanistic basis for these responses by exposing cell lines with single or combined genetic defects in nucleotide excision repair (NER), postreplicative translesion synthesis (TLS), and MMR to low-dose ultraviolet light during S phase. Our data reveal that the MMR heterodimer Msh2/Msh6 mediates the excision of incorrect nucleotides that are incorporated by TLS opposite helix-distorting, noninstructive DNA photolesions. The resulting single-stranded DNA patches induce canonical Rpa-Atr-Chk1-mediated checkpoints and, in the next cell cycle, collapse to double-stranded DNA breaks that trigger apoptosis. In conclusion, a novel MMR-related DNA excision repair pathway controls TLS a posteriori, while initiating cellular responses to environmentally relevant densities of genotoxic lesions. These results may provide a rationale for the colorectal cancer tropism in Lynch syndrome, which is caused by inherited MMR gene defects.
除了校正错配核苷酸外，DNA错配修复（MMR）蛋白还与对诱导结构异常核苷酸损伤的试剂的诱变、细胞周期和凋亡反应有关。在此，我们通过在S期将核苷酸切除修复（NER）、复制后跨损伤合成（TLS）和MMR存在单一或联合基因缺陷的细胞系暴露于低剂量紫外线下，研究了这些反应的机制基础。我们的数据表明，MMR异二聚体Msh2/Msh6介导了由TLS掺入的与扭曲螺旋的非指导性DNA光损伤相对的错误核苷酸的切除。由此产生的单链DNA片段诱导典型的Rpa-Atr-Chk1介导的检查点，并且在下一个细胞周期中，塌陷为双链DNA断裂，从而触发细胞凋亡。总之，一种新的与MMR相关的DNA切除修复途径事后控制TLS，同时启动细胞对环境相关密度的遗传毒性损伤的反应。这些结果可能为林奇综合征中结直肠癌的倾向性提供一个理论依据，林奇综合征是由遗传性MMR基因缺陷引起的。
