Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile

Cramer-Morales, K. et al. (2013) Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. Blood, 122(7), pp. 1293-1304. (doi:10.1182/blood-2013-05-501072)

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Abstract

Homologous recombination repair (HRR) protects cells from 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 addiction of cancer cells to one DNA repair pathway whereas normal cells operate two or more mechanisms. Using mutagenesis and peptide aptamer approach we pinpointed phenylalanine 79 in RAD52 DNA binding domain I (RAD52-F79) as valid target to induce synthetic lethality in BRCA1 and/or BRCA2 –deficient leukemias and carcinomas without affecting normal cells and tissues. Targeting RAD52-F79 disrupts RAD52 - DNA interaction resulting in accumulation of toxic DNA double stand breaks in malignant cells, but not in normal counterparts. In addition, abrogation of RAD52 - DNA interaction enhanced anti-leukemia effect of the 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, and mutations in BRCA1 and/or BRCA2 genes, and also by gene expression profiles identifying leukemias displaying low levels of BRCA1 and/or BRCA2. We believe that this work may initiate personalized therapeutic approach in numerous patients with tumors displaying encoded and functional BRCA-deficiency.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Irvine, Dr David and Copland, Professor Mhairi
Authors: Cramer-Morales, K., Nieborowska-Skorska, M., Scheibner, K., Padget, M., Irvine, D.A., Sliwinski, T., Haas, K., Lee, J., Geng, H., Roy, D., Slupianek, A., Rassool, F.V., Wasik, M.A., Childers, W., Copland, M., Muschen, M., Civin, C.I., and Skorski, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020

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