Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging
Rieckher, Matthias (University of Cologne)
Gallrein, Christian (University and University Hospital of Cologne)
Alquezar-Artieda, Natividad (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Bourached-Silva, Nour (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Vaddavalli, Pavana Lakshmi (University and University Hospital of Cologne)
Mares, Devin (University and University Hospital of Cologne)
Backhaus, Maria (University and University Hospital of Cologne)
Blindauer, Timon (University and University Hospital of Cologne)
Greger, Ksenia (University and University Hospital of Cologne)
Wiesner, Eva (University and University Hospital of Cologne)
Pontel, Lucas B. (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Schumacher, Björn (University of Cologne)

Fecha:	2024
Resumen:	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.
Ayudas:	Agencia Estatal de Investigación PID2022-136694NB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-01309
Nota:	Altres ajuts: European Union NextGeneration EU/PRTR [RYC2021-032395-I, PRTRC17.I1/FANCONI-CURE]; John Templeton Foundation [61734]; Deutsche Krebshilfe [70114555]; Deutsche Forschungsgemeinschaft [496650118, 524088035, EXC 2030 CECAD, FOR 5504, GRK2407, SCHU 2494/10-1, SCHU 2494/11-1, SCHU 2494/15-1, SCHU 2494/3-1, SCHU 2494/7-1]; José Carreras Leukämie-Stiftung [DJCLS 04 R/2023]
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	Nucleic acids research, Vol. 52, Núm. 14 (August 2024) , p. 8271-8285, ISSN 0305-1048

DOI: 10.1093/nar/gkae519
PMID: 38894680

15 p, 2.4 MB

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