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

  • Nowarski R
  • Wilner O
  • Cheshin O
 et al. 
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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

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Authors

  • Roni Nowarski

  • Ofer I. Wilner

  • Ori Cheshin

  • Or D. Shahar

  • Edan Kenig

  • Leah Baraz

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