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

Kimberly Cramer-Morales, Margaret Nieborowska-Skorska, Kara Scheibner, Michelle Padget, David A. Irvine, Tomasz Sliwinski, Kimberly Haas, Jaewoong Lee, Huimin Geng, Darshan Roy, Artur Slupianek, Feyruz V. Rassool, Mariusz A. Wasik, Wayne Childers, Mhairi Copland, Markus Müschen, Curt I. Civin, Tomasz Skorski

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1293-1304
Number of pages12
JournalBlood
Volume122
Issue number7
DOIs
StatePublished - Aug 15 2013
Externally publishedYes

Fingerprint

Transcriptome
Leukemia
Genes
Recombinational DNA Repair
Mutation
DNA
Repair
Phenylalanine
Tumors
Peptide Aptamers
Cells
BRCA2 Gene
BRCA1 Gene
Neoplasms
Mutagenesis
Poisons
Oncogenes
Gene expression
DNA Repair
Genetic Therapy

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Cramer-Morales, K., Nieborowska-Skorska, M., Scheibner, K., Padget, M., Irvine, D. A., Sliwinski, T., ... Skorski, T. (2013). Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. Blood, 122(7), 1293-1304. https://doi.org/10.1182/blood-2013-05-501072

Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. / Cramer-Morales, Kimberly; Nieborowska-Skorska, Margaret; Scheibner, Kara; Padget, Michelle; Irvine, David A.; Sliwinski, Tomasz; Haas, Kimberly; Lee, Jaewoong; Geng, Huimin; Roy, Darshan; Slupianek, Artur; Rassool, Feyruz V.; Wasik, Mariusz A.; Childers, Wayne; Copland, Mhairi; Müschen, Markus; Civin, Curt I.; Skorski, Tomasz.

In: Blood, Vol. 122, No. 7, 15.08.2013, p. 1293-1304.

Research output: Contribution to journalArticle

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 2013, 'Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile.', Blood, vol. 122, no. 7, pp. 1293-1304. https://doi.org/10.1182/blood-2013-05-501072
Cramer-Morales K, Nieborowska-Skorska M, Scheibner K, Padget M, Irvine DA, Sliwinski T et al. Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. Blood. 2013 Aug 15;122(7):1293-1304. https://doi.org/10.1182/blood-2013-05-501072
Cramer-Morales, Kimberly ; Nieborowska-Skorska, Margaret ; Scheibner, Kara ; Padget, Michelle ; Irvine, David A. ; Sliwinski, Tomasz ; Haas, Kimberly ; Lee, Jaewoong ; Geng, Huimin ; Roy, Darshan ; Slupianek, Artur ; Rassool, Feyruz V. ; Wasik, Mariusz A. ; Childers, Wayne ; Copland, Mhairi ; Müschen, Markus ; Civin, Curt I. ; Skorski, Tomasz. / Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. In: Blood. 2013 ; Vol. 122, No. 7. pp. 1293-1304.
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