AI Article Synopsis
- - A patient with a Fanconi anemia-like condition has a new mutation (T131P) in the RAD51 gene, which is crucial for DNA repair through homologous recombination.
- - The mutant RAD51-T131P exhibits unusual properties: it has ATPase activity without the ability to pair DNA and negatively affects the normal RAD51 function in the cell.
- - Despite the mutation, the patient's cells can still perform homologous recombination due to a higher amount of normal RAD51, but they show increased sensitivity to crosslinking agents, signaling the importance of RAD51 in DNA repair beyond the homologous recombination process.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529964 | PMC |
| http://dx.doi.org/10.1016/j.molcel.2015.07.009 | DOI Listing |
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