A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination

Anderson T. Wang, Taeho Kim, John E. Wagner, Brooke A. Conti, Francis P. Lach, Athena L. Huang, Henrik Molina, Erica M. Sanborn, Heather Zierhut, Belinda K. Cornes, Avinash Abhyankar, Carrie Sougnez, Stacey B. Gabriel, Arleen D. Auerbach, Stephen C. Kowalczykowski, Agata Smogorzewska

Research output: Contribution to journalArticle

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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. Invitro, 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 ofmutantto wild-type RAD51 in cells. Instead, patientcells aresensitive 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.

Original languageEnglish (US)
Pages (from-to)478-490
Number of pages13
JournalMolecular Cell
Volume59
Issue number3
DOIs
StatePublished - Aug 6 2015

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Recombinational DNA Repair
Homologous Recombination
Recombinases
Mutation
DNA
DNA Repair
Replication Protein A
Fanconi Anemia
Adenosine Triphosphatases
Phenotype

Cite this

A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination. / Wang, Anderson T.; Kim, Taeho; Wagner, John E.; Conti, Brooke A.; Lach, Francis P.; Huang, Athena L.; Molina, Henrik; Sanborn, Erica M.; Zierhut, Heather; Cornes, Belinda K.; Abhyankar, Avinash; Sougnez, Carrie; Gabriel, Stacey B.; Auerbach, Arleen D.; Kowalczykowski, Stephen C.; Smogorzewska, Agata.

In: Molecular Cell, Vol. 59, No. 3, 06.08.2015, p. 478-490.

Research output: Contribution to journalArticle

Wang, AT, Kim, T, Wagner, JE, Conti, BA, Lach, FP, Huang, AL, Molina, H, Sanborn, EM, Zierhut, H, Cornes, BK, Abhyankar, A, Sougnez, C, Gabriel, SB, Auerbach, AD, Kowalczykowski, SC & Smogorzewska, A 2015, 'A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination', Molecular Cell, vol. 59, no. 3, pp. 478-490. https://doi.org/10.1016/j.molcel.2015.07.009
Wang, Anderson T. ; Kim, Taeho ; Wagner, John E. ; Conti, Brooke A. ; Lach, Francis P. ; Huang, Athena L. ; Molina, Henrik ; Sanborn, Erica M. ; Zierhut, Heather ; Cornes, Belinda K. ; Abhyankar, Avinash ; Sougnez, Carrie ; Gabriel, Stacey B. ; Auerbach, Arleen D. ; Kowalczykowski, Stephen C. ; Smogorzewska, Agata. / A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination. In: Molecular Cell. 2015 ; Vol. 59, No. 3. pp. 478-490.
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