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Cell Rep October 10, 2017; 21 (2): 333-340.

Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection.

Zadorozhny K , Sannino V , Beláň O , Mlčoušková J , Špírek M , Costanzo V , Krejčí L .

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.

PubMed ID: 29020621
Article link: Cell Rep

Species referenced: Xenopus
Genes referenced: dna2 fanca mnd1 mre11 pnp rad51 rel rps3a wrn
GO keywords: DNA replication [+]

Disease Ontology terms: Fanconi anemia complementation group R

Article Images: [+] show captions