title: 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.
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Cramer-Morales
authors.forename: Margaret
authors.initials: M
authors.lastname: Nieborowska-Skorska
authors.forename: Kara
authors.initials: K
authors.lastname: Scheibner
authors.forename: Michelle
authors.initials: M
authors.lastname: Padget
authors.forename: David A
authors.initials: DA
authors.lastname: Irvine
authors.forename: Tomasz
authors.initials: T
authors.lastname: Sliwinski
authors.forename: Kimberly
authors.initials: K
authors.lastname: Haas
authors.forename: Jaewoong
authors.initials: J
authors.lastname: Lee
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.forename: Darshan
authors.initials: D
authors.lastname: Roy
authors.forename: Artur
authors.initials: A
authors.lastname: Slupianek
authors.forename: Feyruz V
authors.initials: FV
authors.lastname: Rassool
authors.forename: Mariusz A
authors.initials: MA
authors.lastname: Wasik
authors.forename: Wayne
authors.initials: W
authors.lastname: Childers
authors.forename: Mhairi
authors.initials: M
authors.lastname: Copland
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.forename: Curt I
authors.initials: CI
authors.lastname: Civin
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000818:Animals; D017209:Apoptosis; D052158:Aptamers, Peptide / Q000737:chemistry / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D057890:Epigenomics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments; D012333:RNA, Messenger / Q000235:genetics; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D051721:Rad52 DNA Repair and Recombination Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011995:Recombination, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D052158:Aptamers, Peptide; C581634:BCR-ABL1 fusion protein, human; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; D010446:Peptide Fragments; D012333:RNA, Messenger; D051721:Rad52 DNA Repair and Recombination Protein; D016044:Fusion Proteins, bcr-abl; D051135:Rad51 Recombinase