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

Abstract:

: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. Targeting RAD52-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.

journal_name

Blood

journal_title

Blood

authors

Cramer-Morales K,Nieborowska-Skorska M,Scheibner K,Padget M,Irvine DA,Sliwinski T,Haas K,Lee J,Geng H,Roy D,Slupianek A,Rassool FV,Wasik MA,Childers W,Copland M,Müschen M,Civin CI,Skorski T

doi

10.1182/blood-2013-05-501072

subject

Has Abstract

pub_date

2013-08-15 00:00:00

pages

1293-304

issue

7

eissn

0006-4971

issn

1528-0020

pii

blood-2013-05-501072

journal_volume

122

pub_type

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