Journal
BLOOD
Volume 122, Issue 7, Pages 1293-1304Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-05-501072
Keywords
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Categories
Funding
- National Institutes of Health [1R01CA134458, 1R21CA133646, R01CA139032, R01CA157644, PO1CA70970]
- Temple University Drug Discovery Initiative
- National Foundation for Cancer Research Fellow Award
- Maryland Stem Cell Research Foundation/TEDCO [2007-MSCRFII-0114, 2012-MSCRFE-0244, 2010-MSCRFII-0065]
- Polish Ministry of Science and Higher Education [607/MOB/2011/0]
- Glasgow Experimental Cancer Medicine Centre
- Cancer Research UK
- Chief Scientist's Office (Scotland) Clinical Research Fellowship
- Scottish Senior Clinical Fellowship
- Scottish Funding Council [SCD/04]
- Chief Scientist Office [SCD/04] Funding Source: researchfish
- NATIONAL CANCER INSTITUTE [R01CA169458, R01CA139032, R01CA137060, R01CA172558, R21CA133646, P01CA070970, T32CA078586, R01CA134458, R01CA157644] Funding Source: NIH RePORTER
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Homologous recombination repair (HRR) protects cells from the lethal effect of spontaneous and therapy-induced DNA double-stand breaks. HRR usually depends on BRCA1/2-RAD51, and RAD52-RAD51 serves as back-up. To target HRR in tumor cells, a phenomenon called synthetic lethality was applied, which relies on the addiction of cancer cells to a single DNA repair pathway, whereas normal cells operate 2 or more mechanisms. Using mutagenesis and a peptide aptamer approach, we pinpointed phenylalanine 79 in RAD52 DNA binding domain I (RAD52-phenylalanine 79 [F79]) as a valid target to induce synthetic lethality in BRCA1- and/or BRCA2-deficient leukemias and carcinomas without affecting normal cells and tissues. TargetingRAD52-F79 disrupts the RAD52-DNA interaction, resulting in the accumulation of toxic DNA double-stand breaks in malignant cells, but not in normal counterparts. In addition, abrogation of RAD52-DNA interaction enhanced the antileukemia effect of already-approved drugs. BRCA-deficient status predisposing to RAD52-dependent synthetic lethality could be predicted by genetic abnormalities such as oncogenes BCR-ABL1 and PML-RAR, mutations in BRCA1 and/or BRCA2 genes, and gene expression profiles identifying leukemias displaying low levels of BRCA1 and/or BRCA2. We believe this work may initiate a personalized therapeutic approach in numerous patients with tumors displaying encoded and functional BRCA deficiency.
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