APOBEC3G hypermutates genomic DNA and inhibits Ty1 retrotransposition in yeast

被引:117
作者
Schumacher, AJ
Nissley, DV
Harris, RS [1 ]
机构
[1] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Inst Mol Virol, Minneapolis, MN 55455 USA
[3] NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA
[4] NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA
基金
英国惠康基金;
关键词
APOBEC3F; endogenous retrotransposon Ty1; hypermutation; cytodeamination; Saccharomyces cerevisiae;
D O I
10.1073/pnas.0501694102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Human cells harbor a variety of factors that function to block the proliferation of foreign nucleic acid. The APOBEC3G enzyme inhibits the replication of retroviruses by deaminating nascent retroviral cDNA cytosines to uracils, lesions that can result in lethal levels of hypermutation. Here, we demonstrate that APOBEC3G is capable of deaminating genomic cytosines in Saccharomyces cerevisiae. APOBEC3G expression caused a 20-fold increase in frequency of mutation to canavanine-resistance, which was further elevated in a uracil DNA glycosylase-deficient background. All APOBEC3G-induced base substitution mutations mapped to the nuclear CAN1 gene and were exclusively C/G -> T/A transition mutations within a 5'-CC consensus. The APOBEC3G preferred sites were found on both strands of the DNA duplex, but were otherwise located in hotspots nearly identical to those found previously in retroviral cDNA. This unique genetic system further enabled us to show that expression of APOBEC3G or its homolog APOBEC3F was able to inhibit the mobility of the retrotransposon Ty1 by a mechanism that involves the deamination of cDNA cytosines. Thus, these data expand the range of likely APOBEC3 targets to include nuclear DNA and endogenous retroelements, which have pathological and physiological implications, respectively. We postulate that the APOBEC3-dependent innate cellular defense constitutes a tightly regulated arm of a conserved mobile nucleic acid restriction mechanism that is poised to limit internal as well as external assaults.
引用
收藏
页码:9854 / 9859
页数:6
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