APOBEC3G enhances lymphoma cell radioresistance by promoting cytidine deaminase-dependent DNA repair.
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 physiologic 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 and enhanced survival of irradiated cells. APOBEC3G transiently accumulated in the nucleus in response to ionizing radiation 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 prosurvival factor in lymphoma cells, marking APOBEC3G as a potential target for sensitizing lymphoma to radiation therapy.
Department of Pathology and the Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Roni
R
Nowarski
Ofer I
OI
Wilner
Ori
O
Cheshin
Or D
OD
Shahar
Edan
E
Kenig
Leah
L
Baraz
Elena
E
Britan-Rosich
Arnon
A
Nagler
Reuben S
RS
Harris
Michal
M
Goldberg
Itamar
I
Willner
Moshe
M
Kotler
D000071480:APOBEC-3G Deaminase; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004260:DNA Repair / Q000502:physiology*; D004273:DNA, Neoplasm / Q000378:metabolism / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D018625:Microscopy, Atomic Force; D055503:Protein Multimerization; D011836:Radiation Tolerance / Q000502:physiology*
D004273:DNA, Neoplasm; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase