Blood Journal
Leading the way in experimental and clinical research in hematology

APOBEC3G enhances lymphoma cell radioresistance by promoting cytidine deaminase-dependent DNA repair

  1. Roni Nowarski1,
  2. Ofer I. Wilner2,
  3. Ori Cheshin1,
  4. Or D. Shahar3,
  5. Edan Kenig1,
  6. Leah Baraz1,
  7. Elena Britan-Rosich1,
  8. Arnon Nagler4,
  9. Reuben S. Harris5,
  10. Michal Goldberg3,
  11. Itamar Willner2, and
  12. Moshe Kotler1,*
  1. 1 Department of Pathology and the Lautenberg Center for General and Tumor Immunology, the Hebrew University-Hadassah Medical School, Jerusalem, Israel;
  2. 2 Institute of Chemistry and Center for Nanoscience and Nanotechnology, the Hebrew University, Jerusalem, Israel;
  3. 3 The Department of Genetics, The Institute of Life Sciences, The Hebrew University, Jerusalem, Israel;
  4. 4 The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel;
  5. 5 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, United States
  1. * Corresponding author; email: moshek{at}ekmd.huji.ac.il

Abstract

APOBEC3 proteins catalyze deamination of cytidines in single-stranded DNA (ssDNA), providing innate protection against retroviral replication by inducing deleterious dC>dU hypermutation of replication intermediates. APOBEC3G expression is induced in mitogen-activated lymphocytes, however no physiological role related to lymphoid cell proliferation has yet to be determined. Moreover, whether APOBEC3G cytidine deaminase activity transcends to processing cellular genomic DNA is unknown. Here we show that lymphoma cells expressing high APOBEC3G levels display efficient repair of genomic DNA double strand breaks (DSBs) induced by ionizing radiation (IR) and enhanced survival of irradiated cells. APOBEC3G transiently accumulated in the nucleus in response to IR and was recruited to DSB repair foci. Consistent with a direct role in DSB repair, inhibition of APOBEC3G expression or deaminase activity resulted in deficient DSB repair, whereas reconstitution of APOBEC3G expression in leukemia cells enhanced DSB repair. APOBEC3G activity involved processing of DNA flanking a DSB in an integrated reporter cassette. Atomic force microscopy indicated that APOBEC3G multimers associate with ssDNA termini, triggering multimer disassembly to multiple catalytic units. These results identify APOBEC3G as a pro-survival factor in lymphoma cells, marking APOBEC3G as a potential target for sensitizing lymphoma to radiation therapy.

  • Submitted January 4, 2012.
  • Accepted May 15, 2012.