Rad52 inactivation is synthetically lethal with BRCA2 deficiency — PNAS

Rad52 inactivation is synthetically lethal with BRCA2 deficiency

1. Zhihui Fenga,1,
2. Shaun P. Scotta,
3. Wendy Bussena,
4. Girdhar G. Sharmaa,
5. Gongshe Guoa,
6. Tej K. Panditaa,2, and
7. Simon N. Powella,b,3

+ Author Affiliations

1. aDepartment of Radiation Oncology, Washington University, St. Louis, MO 63108; and
2. bDepartment of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065

* ↵1Present address: School of Public Health, Shandong University, Jinan 250012, China.
* ↵2Present address: Department of Radiation Oncology, University of Texas Southwestern, Dallas, TX 75390.

1. Edited by Stephen C. Kowalczykowski, University of California, Davis, CA, and approved November 2, 2010 (received for review July 25, 2010)

Abstract

Synthetic lethality is a powerful approach to study selective cell killing based on genotype. We show that loss of Rad52 function is synthetically lethal with breast cancer 2, early onset (BRCA2) deficiency, whereas there was no impact on cell growth and viability in BRCA2-complemented cells. The frequency of both spontaneous and double-strand break-induced homologous recombination and ionizing radiation-induced Rad51 foci decreased by 2–10 times when Rad52 was depleted in BRCA2-deficient cells, with little to no effect in BRCA2-complemented cells. The absence of both Rad52 and BRCA2 resulted in extensive chromosome aberrations, especially chromatid-type aberrations. Ionizing radiation-induced and S phase-associated Rad52-Rad51 foci form equally well in the presence or absence of BRCA2, indicating that Rad52 can respond to DNA double-strand breaks and replication stalling independently of BRCA2. Rad52 thus is an independent and alternative repair pathway of homologous recombination and a target for therapy in BRCA2-deficient cells.

* DNA repair
* genetic instability
* chromosomal aberrations

Footnotes

* 3To whom correspondence should be addressed. E-mail: powells@mskcc.org.
* Author contributions: Z.F. and S.N.P. designed research; Z.F., G.G.S., and G.G. performed research; Z.F., S.P.S., W.B., T.K.P., and S.N.P. analyzed data; and Z.F., S.P.S., W.B., and S.N.P. wrote the paper.
* The authors declare no conflict of interest.
* See Commentary on page 441.
* This article is a PNAS Direct Submission.
* This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1010959107/-/DCSupplemental.

Freely available online through the PNAS open access option.

Rad52 inactivation is synthetically lethal with BRCA2 deficiency — PNAS