Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging

Autores
Rieckher, Matthias; Gallrein, Christian; Alquezar Artieda, Natividad; Bourached Silva, Nour; Vaddavalli, Pavana Lakshmi; Mares, Devin; Backhaus, Maria; Blindauer, Timon; Greger, Ksenia; Wiesner, Eva; Pontel, Lucas Blas; Schumacher, Björn
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Rieckher, Matthias. Universitat zu Köln; Alemania
Fil: Gallrein, Christian. Universitat zu Köln; Alemania
Fil: Alquezar Artieda, Natividad. No especifíca;
Fil: Bourached Silva, Nour. No especifíca;
Fil: Vaddavalli, Pavana Lakshmi. Universitat zu Köln; Alemania
Fil: Mares, Devin. Universitat zu Köln; Alemania
Fil: Backhaus, Maria. Universitat zu Köln; Alemania
Fil: Blindauer, Timon. Universitat zu Köln; Alemania
Fil: Greger, Ksenia. Universitat zu Köln; Alemania
Fil: Wiesner, Eva. Universitat zu Köln; Alemania
Fil: Pontel, Lucas Blas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Schumacher, Björn. Universitat zu Köln; Alemania
Materia
Fanconi anemia
DNA repair
formaldehyde
ADH5
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/258906
Acceder
id CONICETDig_115dce43616042317ab69335ee964292
oai_identifier_str oai:ri.conicet.gov.ar:11336/258906
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and agingRieckher, MatthiasGallrein, ChristianAlquezar Artieda, NatividadBourached Silva, NourVaddavalli, Pavana LakshmiMares, DevinBackhaus, MariaBlindauer, TimonGreger, KseniaWiesner, EvaPontel, Lucas BlasSchumacher, BjörnFanconi anemiaDNA repairformaldehydeADH5https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Formaldehyde (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.Fil: Rieckher, Matthias. Universitat zu Köln; AlemaniaFil: Gallrein, Christian. Universitat zu Köln; AlemaniaFil: Alquezar Artieda, Natividad. No especifíca;Fil: Bourached Silva, Nour. No especifíca;Fil: Vaddavalli, Pavana Lakshmi. Universitat zu Köln; AlemaniaFil: Mares, Devin. Universitat zu Köln; AlemaniaFil: Backhaus, Maria. Universitat zu Köln; AlemaniaFil: Blindauer, Timon. Universitat zu Köln; AlemaniaFil: Greger, Ksenia. Universitat zu Köln; AlemaniaFil: Wiesner, Eva. Universitat zu Köln; AlemaniaFil: Pontel, Lucas Blas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Schumacher, Björn. Universitat zu Köln; AlemaniaOxford University Press2024-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/258906Rieckher, Matthias; Gallrein, Christian; Alquezar Artieda, Natividad; Bourached Silva, Nour; Vaddavalli, Pavana Lakshmi; et al.; Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging; Oxford University Press; Nucleic Acids Research; 52; 14; 8-2024; 8271-82850305-10481362-4962CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/nar/article/52/14/8271/7696021info:eu-repo/semantics/altIdentifier/doi/10.1093/nar/gkae519info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:25:00Zoai:ri.conicet.gov.ar:11336/258906instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:25:00.849CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging
title Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging
spellingShingle Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging
Rieckher, Matthias
Fanconi anemia
DNA repair
formaldehyde
ADH5
title_short Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging
title_full Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging
title_fullStr Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging
title_full_unstemmed Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging
title_sort Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging
dc.creator.none.fl_str_mv Rieckher, Matthias
Gallrein, Christian
Alquezar Artieda, Natividad
Bourached Silva, Nour
Vaddavalli, Pavana Lakshmi
Mares, Devin
Backhaus, Maria
Blindauer, Timon
Greger, Ksenia
Wiesner, Eva
Pontel, Lucas Blas
Schumacher, Björn
author Rieckher, Matthias
author_facet Rieckher, Matthias
Gallrein, Christian
Alquezar Artieda, Natividad
Bourached Silva, Nour
Vaddavalli, Pavana Lakshmi
Mares, Devin
Backhaus, Maria
Blindauer, Timon
Greger, Ksenia
Wiesner, Eva
Pontel, Lucas Blas
Schumacher, Björn
author_role author
author2 Gallrein, Christian
Alquezar Artieda, Natividad
Bourached Silva, Nour
Vaddavalli, Pavana Lakshmi
Mares, Devin
Backhaus, Maria
Blindauer, Timon
Greger, Ksenia
Wiesner, Eva
Pontel, Lucas Blas
Schumacher, Björn
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Fanconi anemia
DNA repair
formaldehyde
ADH5
topic Fanconi anemia
DNA repair
formaldehyde
ADH5
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Rieckher, Matthias. Universitat zu Köln; Alemania
Fil: Gallrein, Christian. Universitat zu Köln; Alemania
Fil: Alquezar Artieda, Natividad. No especifíca;
Fil: Bourached Silva, Nour. No especifíca;
Fil: Vaddavalli, Pavana Lakshmi. Universitat zu Köln; Alemania
Fil: Mares, Devin. Universitat zu Köln; Alemania
Fil: Backhaus, Maria. Universitat zu Köln; Alemania
Fil: Blindauer, Timon. Universitat zu Köln; Alemania
Fil: Greger, Ksenia. Universitat zu Köln; Alemania
Fil: Wiesner, Eva. Universitat zu Köln; Alemania
Fil: Pontel, Lucas Blas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Schumacher, Björn. Universitat zu Köln; Alemania
description 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.
publishDate 2024
dc.date.none.fl_str_mv 2024-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/258906
Rieckher, Matthias; Gallrein, Christian; Alquezar Artieda, Natividad; Bourached Silva, Nour; Vaddavalli, Pavana Lakshmi; et al.; Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging; Oxford University Press; Nucleic Acids Research; 52; 14; 8-2024; 8271-8285
0305-1048
1362-4962
CONICET Digital
CONICET
url http://hdl.handle.net/11336/258906
identifier_str_mv Rieckher, Matthias; Gallrein, Christian; Alquezar Artieda, Natividad; Bourached Silva, Nour; Vaddavalli, Pavana Lakshmi; et al.; Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging; Oxford University Press; Nucleic Acids Research; 52; 14; 8-2024; 8271-8285
0305-1048
1362-4962
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/nar/article/52/14/8271/7696021
info:eu-repo/semantics/altIdentifier/doi/10.1093/nar/gkae519
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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