Selvam Kathiresan, Plummer Dalton A, Mao Peng, Wyrick John J
School of Molecular Biosciences, Washington State University, Pullman, Washington, United States of America.
Department of Internal Medicine, Program in Cellular and Molecular Oncology, University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, United States of America.
PLoS Genet. 2022 Mar 9;18(3):e1010085. doi: 10.1371/journal.pgen.1010085. eCollection 2022 Mar.
Helix-distorting DNA lesions, including ultraviolet (UV) light-induced damage, are repaired by the global genomic-nucleotide excision repair (GG-NER) and transcription coupled-nucleotide excision repair (TC-NER) pathways. Previous studies have shown that histone post-translational modifications (PTMs) such as histone acetylation and methylation can promote GG-NER in chromatin. Whether histone PTMs also regulate the repair of DNA lesions by the TC-NER pathway in transcribed DNA is unknown. Here, we report that histone H3 K36 methylation (H3K36me) by the Set2 histone methyltransferase in yeast regulates TC-NER. Mutations in Set2 or H3K36 result in UV sensitivity that is epistatic with Rad26, the primary TC-NER factor in yeast, and cause a defect in the repair of UV damage across the yeast genome. We further show that mutations in Set2 or H3K36 in a GG-NER deficient strain (i.e., rad16Δ) partially rescue its UV sensitivity. Our data indicate that deletion of SET2 rescues UV sensitivity in a GG-NER deficient strain by activating cryptic antisense transcription, so that the non-transcribed strand (NTS) of yeast genes is repaired by TC-NER. These findings indicate that Set2 methylation of H3K36 establishes transcriptional asymmetry in repair by promoting canonical TC-NER of the transcribed strand (TS) and suppressing cryptic TC-NER of the NTS.
包括紫外线（UV）诱导损伤在内的螺旋扭曲型DNA损伤，可通过全基因组核苷酸切除修复（GG-NER）和转录偶联核苷酸切除修复（TC-NER）途径进行修复。先前的研究表明，组蛋白翻译后修饰（PTM），如组蛋白乙酰化和甲基化，可促进染色质中的GG-NER。组蛋白PTM是否也通过TC-NER途径调节转录DNA中DNA损伤的修复尚不清楚。在此，我们报道酵母中Set2组蛋白甲基转移酶介导的组蛋白H3 K36甲基化（H3K36me）调节TC-NER。Set2或H3K36中的突变导致紫外线敏感性，该敏感性与酵母中的主要TC-NER因子Rad26上位，并且在整个酵母基因组的紫外线损伤修复中导致缺陷。我们进一步表明，GG-NER缺陷菌株（即rad16Δ）中Set2或H3K36的突变部分挽救了其紫外线敏感性。我们的数据表明，SET2的缺失通过激活隐蔽的反义转录来挽救GG-NER缺陷菌株中的紫外线敏感性，从而使酵母基因的非转录链（NTS）通过TC-NER进行修复。这些发现表明，H3K36的Set2甲基化通过促进转录链（TS）的经典TC-NER和抑制NTS的隐蔽TC-NER，在修复中建立转录不对称性。
