Reference - Detail
| RRC ID | 84010 |
|---|---|
| Author | Rieckher M, Gallrein C, Alquezar-Artieda N, Bourached-Silva N, Vaddavalli PL, Mares D, Backhaus M, Blindauer T, Greger K, Wiesner E, Pontel LB, Schumacher B. |
| Title | Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging. |
| Journal | Nucleic Acids Res |
| Abstract |
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. |
| Volume | 52(14) |
| Pages | 8271-8285 |
| Published | 2024-8-12 |
| DOI | 10.1093/nar/gkae519 |
| PII | 7696021 |
| PMID | 38894680 |
| PMC | PMC11317141 |
| MeSH | Acetylcysteine / pharmacology Aging* / genetics Aldehyde Dehydrogenase / genetics Aldehyde Dehydrogenase / metabolism Aldehyde Oxidoreductases Animals Caenorhabditis elegans* / drug effects Caenorhabditis elegans* / genetics Caenorhabditis elegans* / growth & development Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism DNA Damage* DNA Repair* Formaldehyde* / toxicity Humans Mutation Reproduction* / drug effects Reproduction* / genetics Transcription, Genetic / drug effects |
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 45 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tm2644 tm2940 tm1981 tm6311 tm1842 tm3886 tm1298 tm1670 |