Universität zu Köln

Wilson, David M., III, Rieckher, Matthias ORCID: 0000-0002-1945-9474, Williams, Ashley B. and Schumacher, Bjoern (2017). Systematic analysis of DNA crosslink repair pathways during development and aging in Caenorhabditis elegans. Nucleic Acids Res., 45 (16). S. 9467 - 9481. OXFORD: OXFORD UNIV PRESS. ISSN 1362-4962

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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 geno-toxicity 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 de-velopment and in adult post-mitotic and proliferative germ cells.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wilson, David M., III UNSPECIFIED UNSPECIFIED UNSPECIFIED Rieckher, Matthias UNSPECIFIED orcid.org/0000-0002-1945-9474 UNSPECIFIED Williams, Ashley B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schumacher, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-217557
DOI:	10.1093/nar/gkx660
Journal or Publication Title:	Nucleic Acids Res.
Volume:	45
Number:	16
Page Range:	S. 9467 - 9481
Date:	2017
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1362-4962
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NUCLEOTIDE EXCISION-REPAIR; TRANSCRIPTION-COUPLED REPAIR; FANCONI-ANEMIA PATHWAY; MISMATCH REPAIR; HUMAN-CELLS; TRANSLESION SYNTHESIS; REPLICATION STRESS; MAMMALIAN-CELLS; C. ELEGANS; DUPLEX DNA Multiple languages Biochemistry & Molecular Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21755