RRC ID 51490
Author Wilson DM 3rd, Rieckher M, Williams AB, Schumacher B.
Title Systematic analysis of DNA crosslink repair pathways during development and aging in Caenorhabditis elegans.
Journal Nucleic Acids Res
Abstract DNA interstrand crosslinks (ICLs) are generated by endogenous sources and chemotherapeutics, and pose a threat to genome stability and cell survival. Using Caenorhabditis elegans mutants, we identify DNA repair factors that protect against the genotoxicity of ICLs generated by trioxsalen/ultraviolet A (TMP/UVA) during development and aging. Mutations in nucleotide excision repair (NER) components (e.g. XPA-1 and XPF-1) imparted extreme sensitivity to TMP/UVA relative to wild-type animals, manifested as developmental arrest, defects in adult tissue morphology and functionality, and shortened lifespan. Compensatory roles for global-genome (XPC-1) and transcription-coupled (CSB-1) NER in ICL sensing were exposed. The analysis also revealed contributions of homologous recombination (BRC-1/BRCA1), the MUS-81, EXO-1, SLX-1 and FAN-1 nucleases, and the DOG-1 (FANCJ) helicase in ICL resolution, influenced by the replicative-status of the cell/tissue. No obvious or critical role in ICL repair was seen for non-homologous end-joining (cku-80) or base excision repair (nth-1, exo-3), the Fanconi-related proteins BRC-2 (BRCA2/FANCD1) and FCD-2 (FANCD2), the WRN-1 or HIM-6 (BLM) helicases, or the GEN-1 or MRT-1 (SNM1) nucleases. Our efforts uncover replication-dependent and -independent ICL repair networks, and establish nematodes as a model for investigating the repair and consequences of DNA crosslinks in metazoan development and in adult post-mitotic and proliferative germ cells.
Volume 45(16)
Pages 9467-9480
Published 2017-9-19
DOI 10.1093/nar/gkx660
PII 4056235
PMID 28934497
PMC PMC5766164
MeSH Aging* / drug effects Aging* / physiology Aging* / radiation effects Animals Caenorhabditis elegans / drug effects Caenorhabditis elegans / growth & development Caenorhabditis elegans / physiology* Caenorhabditis elegans / radiation effects Caenorhabditis elegans Proteins / genetics DNA / chemistry DNA Repair* / drug effects DNA Repair* / radiation effects Female Homologous Recombination Male Mutation Trioxsalen / pharmacology Ultraviolet Rays
IF 11.502
Times Cited 5
C.elegans tm1086 tm1145 tm1298 tm1354 tm1670 tm1842 tm1937 tm1981 tm2073 tm2181 tm2644 tm2842 tm2940 tm3886 tm423 tm5232