Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články
PubMed
29020621
DOI
10.1016/j.celrep.2017.09.062
PII: S2211-1247(17)31352-9
Knihovny.cz E-zdroje
- Klíčová slova
- Fanconi anemia, RAD51, recombination, replication,
- MeSH
- adenosintrifosfát metabolismus MeSH
- Fanconiho anemie genetika MeSH
- homologní protein MRE11 metabolismus MeSH
- lidé MeSH
- mutace * MeSH
- rekombinasa Rad51 genetika metabolismus MeSH
- replikace DNA * MeSH
- stabilita proteinů MeSH
- vazba proteinů MeSH
- Xenopus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adenosintrifosfát MeSH
- homologní protein MRE11 MeSH
- MRE11 protein, human MeSH Prohlížeč
- RAD51 protein, human MeSH Prohlížeč
- rekombinasa Rad51 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
Citace poskytuje 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
