Differential Requirements for the RAD51 Paralogs in Genome Repair and Maintenance in Human Cells

Deficiency in several of the classical human RAD51 paralogs [RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3] is associated with cancer predisposition and Fanconi anemia. To investigate their functions, isogenic disruption mutants for each were generated in non-transformed MCF10A mammary epithelial cells an...

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Vydáno v:	PLoS genetics Ročník 15; číslo 10; s. e1008355
Hlavní autoři:	Garcin, Edwige B., Gon, Stéphanie, Sullivan, Meghan R., Brunette, Gregory J., Cian, Anne De, Concordet, Jean-Paul, Giovannangeli, Carine, Dirks, Wilhelm G., Eberth, Sonja, Bernstein, Kara A., Prakash, Rohit, Jasin, Maria, Modesti, Mauro
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 04.10.2019 Public Library of Science (PLoS)
Témata:	Anemia Biochemistry, Molecular Biology Biology and Life Sciences Cancer Cell culture Cell Nucleus - genetics Cells (Biology) Chemoresistance Chemotherapy Chromatids - genetics Cloning CRISPR Deoxyribonucleic acid Developmental biology DNA DNA Damage - genetics DNA repair DNA Repair - genetics DNA-Binding Proteins - genetics Epithelial cells Fanconi syndrome Fanconi's anemia Funding Genes Genome, Human - genetics Genomes Genomics HEK293 Cells Homologous Recombination - genetics Humans Ionizing radiation Life Sciences Mammary gland Medical equipment industry Medical research Medicine and Health Sciences Microorganisms Mitomycin Mitomycin C Molecular biology Museums Mutation Olaparib Phenotypes Physical Sciences Rad51 Recombinase - genetics Recombination Research and Analysis Methods Supervision United States New York Pittsburgh Pennsylvania France United States > US Germany Pennsylvania Polymerase chain reaction Cell disruption Cloning Guide RNA Plasmid construction Genetic loci Complement system Analysis of variance
ISSN:	1553-7404, 1553-7390, 1553-7404
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Shrnutí:	Deficiency in several of the classical human RAD51 paralogs [RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3] is associated with cancer predisposition and Fanconi anemia. To investigate their functions, isogenic disruption mutants for each were generated in non-transformed MCF10A mammary epithelial cells and in transformed U2OS and HEK293 cells. In U2OS and HEK293 cells, viable ablated clones were readily isolated for each RAD51 paralog; in contrast, with the exception of RAD51B, RAD51 paralogs are cell-essential in MCF10A cells. Underlining their importance for genomic stability, mutant cell lines display variable growth defects, impaired sister chromatid recombination, reduced levels of stable RAD51 nuclear foci, and hyper-sensitivity to mitomycin C and olaparib, with the weakest phenotypes observed in RAD51B-deficient cells. Altogether these observations underscore the contributions of RAD51 paralogs in diverse DNA repair processes, and demonstrate essential differences in different cell types. Finally, this study will provide useful reagents to analyze patient-derived mutations and to investigate mechanisms of chemotherapeutic resistance deployed by cancers.
Bibliografie:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 The authors declare no competing interests.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1008355