A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination
Autor: | Belinda K. Cornes, Agata Smogorzewska, Stephen C. Kowalczykowski, Carrie Sougnez, Taeho Kim, Henrik Molina, Brooke A. Conti, Avinash Abhyankar, Francis P. Lach, Erica Sanborn, Athena L. Huang, Arleen D. Auerbach, Anderson T. Wang, Heather Zierhut, John E. Wagner, Stacey Gabriel |
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Rok vydání: | 2015 |
Předmět: |
Heterozygote
Werner Syndrome Helicase DNA Repair Cell Survival DNA repair genetic processes RAD51 Biology Medical and Health Sciences Genetic recombination Article Genomic Instability Homology directed repair Replication Protein A Genetics Humans Molecular Biology Replication protein A RecQ Helicases DNA Helicases Infant DNA Hematology Cell Biology Biological Sciences DNA repair protein XRCC4 Molecular biology Non-homologous end joining enzymes and coenzymes (carbohydrates) Fanconi Anemia Exodeoxyribonucleases Cross-Linking Reagents HEK293 Cells Mutation health occupations Female Rad51 Recombinase Generic health relevance Homologous recombination Developmental Biology |
Zdroj: | Molecular cell, vol 59, iss 3 |
ISSN: | 1097-2765 |
Popis: | Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. In vitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio of mutant to wild-type RAD51 in cells. Instead, patient cells are sensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity. |
Databáze: | OpenAIRE |
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