Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection
Language English Country United States Media print
Document type Journal Article
PubMed
29020621
DOI
10.1016/j.celrep.2017.09.062
PII: S2211-1247(17)31352-9
Knihovny.cz E-resources
- Keywords
- Fanconi anemia, RAD51, recombination, replication,
- MeSH
- Adenosine Triphosphate metabolism MeSH
- Fanconi Anemia genetics MeSH
- MRE11 Homologue Protein metabolism MeSH
- Humans MeSH
- Mutation * MeSH
- Rad51 Recombinase genetics metabolism MeSH
- DNA Replication * MeSH
- Protein Stability MeSH
- Protein Binding MeSH
- Xenopus MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Adenosine Triphosphate MeSH
- MRE11 Homologue Protein MeSH
- MRE11 protein, human MeSH Browser
- RAD51 protein, human MeSH Browser
- Rad51 Recombinase MeSH
Fanconi anemia (FA) is a genetic disorder characterized by a defect in DNA interstrand crosslink (ICL) repair, chromosomal instability, and a predisposition to cancer. Recently, two RAD51 mutations were reported to cause an FA-like phenotype. Despite the tight association of FA/HR proteins with replication fork (RF) stabilization during normal replication, it remains unknown how FA-associated RAD51 mutations affect replication beyond ICL lesions. Here, we report that these mutations fail to protect nascent DNA from MRE11-mediated degradation during RF stalling in Xenopus laevis egg extracts. Reconstitution of DNA protection in vitro revealed that the defect arises directly due to altered RAD51 properties. Both mutations induce pronounced structural changes and RAD51 filament destabilization that is not rescued by prevention of ATP hydrolysis due to aberrant ATP binding. Our results further interconnect the FA pathway with DNA replication and provide mechanistic insight into the role of RAD51 in recombination-independent mechanisms of genome maintenance.
Department of Biology Masaryk University 62500 Brno Czech Republic
DNA Metabolism Laboratory IFOM The Firc Institute of Molecular Oncology 20139 Milan Italy
References provided by Crossref.org
Mechanism of BCDX2-mediated RAD51 nucleation on short ssDNA stretches and fork DNA
RAD51 separation of function mutation disables replication fork maintenance but preserves DSB repair
