Institute for Genome Stability in Aging and Disease, Medical Faculty, University and University Hospital of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
Nucleic Acids Res. 2024 Aug 12;52(14):8271-8285. doi: 10.1093/nar/gkae519.
Formaldehyde (FA) is a recognized environmental and metabolic toxin implicated in cancer development and aging. Inherited mutations in the FA-detoxifying enzymes ADH5 and ALDH2 genes lead to FA overload in the severe multisystem AMeD syndrome. FA accumulation causes genome damage including DNA-protein-, inter- and intra-strand crosslinks and oxidative lesions. However, the influence of distinct DNA repair systems on organismal FA resistance remains elusive. We have here investigated the consequence of a range of DNA repair mutants in a model of endogenous FA overload generated by downregulating the orthologs of human ADH5 and ALDH2 in C. elegans. We have focused on the distinct components of nucleotide excision repair (NER) during developmental growth, reproduction and aging. Our results reveal three distinct modes of repair of FA-induced DNA damage: Transcription-coupled repair (TCR) operating NER-independently during developmental growth or through NER during adulthood, and, in concert with global-genome (GG-) NER, in the germline and early embryonic development. Additionally, we show that the Cockayne syndrome B (CSB) factor is involved in the resolution of FA-induced DNA-protein crosslinks, and that the antioxidant and FA quencher N-acetyl-l-cysteine (NAC) reverses the sensitivity of detoxification and DNA repair defects during development, suggesting a therapeutic intervention to revert FA-pathogenic consequences.
甲醛（FA）是一种公认的环境和代谢毒素，与癌症的发生和衰老有关。ADH5 和 ALDH2 基因中 FA 解毒酶的遗传突变导致严重的多系统 AMeD 综合征中 FA 过载。FA 积累会导致基因组损伤，包括 DNA-蛋白质、链间和链内交联以及氧化损伤。然而，不同的 DNA 修复系统对生物体 FA 抗性的影响仍不清楚。我们在这里研究了一系列 DNA 修复突变体在通过下调秀丽隐杆线虫中人类 ADH5 和 ALDH2 的同源物引起的内源性 FA 过载模型中的后果。我们专注于发育生长、生殖和衰老过程中核苷酸切除修复（NER）的不同组成部分。我们的结果揭示了 FA 诱导的 DNA 损伤的三种不同修复模式：转录偶联修复（TCR）在发育生长过程中独立于 NER 或在成年期通过 NER 进行，并且与全基因组（GG-NER）一起在生殖系和早期胚胎发育中进行。此外，我们表明 Cockayne 综合征 B（CSB）因子参与 FA 诱导的 DNA-蛋白质交联的解决，并且抗氧化剂和 FA 淬灭剂 N-乙酰-l-半胱氨酸（NAC）在发育过程中逆转解毒和 DNA 修复缺陷的敏感性，表明可以进行治疗干预以逆转 FA 致病后果。
