Universität zu Köln

Wolters, Stefanie, Ermolaeva, Maria A., Bickel, Jeremy S., Fingerhut, Jaclyn M., Khanikar, Jayshree, Chan, Raymond C. and Schumacher, Bjoern (2014). Loss of Caenorhabditis elegans BRCA1 Promotes Genome Stability During Replication in smc-5 Mutants. Genetics, 196 (4). S. 985 - 1013. BETHESDA: GENETICS SOCIETY AMERICA. ISSN 1943-2631

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Abstract

DNA damage by ultraviolet (UV) light poses a risk for mutagenesis and a potential hindrance for cell cycle progression. Cells cope with UV-induced DNA damage through two general strategies to repair the damaged nucleotides and to promote cell cycle progression in the presence of UV-damaged DNA. Defining the genetic pathways and understanding how they function together to enable effective tolerance to UV remains an important area of research. The structural maintenance of chromosomes (SMC) proteins form distinct complexes that maintain genome stability during chromosome segregation, homologous recombination, and DNA replication. Using a forward genetic screen, we identified two alleles of smc-5 that exacerbate UV sensitivity in Caenorhabditis elegans. Germ cells of smc-5-defective animals show reduced proliferation, sensitivity to perturbed replication, chromatin bridge formation, and accumulation of RAD-51 foci that indicate the activation of homologous recombination at DNA double-strand breaks. Mutations in the translesion synthesis polymerase polh-1 act synergistically with smc-5 mutations in provoking genome instability after UV-induced DNA damage. In contrast, the DNA damage accumulation and sensitivity of smc-5 mutant strains to replication impediments are suppressed by mutations in the C. elegans BRCA1/BARD1 homologs, brc-1 and brd-1. We propose that SMC-5/6 promotes replication fork stability and facilitates recombination-dependent repair when the BRC-1/BRD-1 complex initiates homologous recombination at stalled replication forks. Our data suggest that BRC-1/BRD-1 can both promote and antagonize genome stability depending on whether homologous recombination is initiated during DNA double-strand break repair or during replication stalling.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wolters, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Ermolaeva, Maria A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bickel, Jeremy S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fingerhut, Jaclyn M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Khanikar, Jayshree UNSPECIFIED UNSPECIFIED UNSPECIFIED Chan, Raymond C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schumacher, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-442246
DOI:	10.1534/genetics.113.158295
Journal or Publication Title:	Genetics
Volume:	196
Number:	4
Page Range:	S. 985 - 1013
Date:	2014
Publisher:	GENETICS SOCIETY AMERICA
Place of Publication:	BETHESDA
ISSN:	1943-2631
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-DAMAGE RESPONSE; DOUBLE-STRAND BREAKS; NUCLEOTIDE EXCISION-REPAIR; SACCHAROMYCES-CEREVISIAE; HOMOLOGOUS RECOMBINATION; POSTREPLICATION REPAIR; CHECKPOINT RESPONSES; SMC5/6 COMPLEX; RAD18; CHROMOSOME Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44224