A Critical Role for REV1 in Regulating the Induction of C:G Transitions and A:T Mutations during Ig Gene Hypermutation
A Critical Role for REV1 in Regulating the Induction of C:G Transitions and A:T Mutations during Ig Gene Hypermutation
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DOI：
10.4049/jimmunol.0901240
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发表时间：
2009-08-01
影响因子：
4.4
通讯作者：
Wang, Ji-Yang
中科院分区：
文献类型：
--
作者：
Masuda, Keiji;Ouchida, Rika;Wang, Ji-Yang
REV 1是一种脱氧胞苷酰转移酶，催化脱氧胞苷与脱氧鸟嘌呤和脱碱基位点相对的掺入。为了探索其催化活性在哺乳动物细胞中IG基因超突变中的作用，我们产生了表达无催化活性的REV 1（REV 1AA）的小鼠。REV 1AA小鼠发育正常，在纯C57 BL/6遗传背景下具有生育能力。B和T细胞发育和成熟不受影响，REV 1AA B细胞进行正常活化和类别转换重组。对REV 1AA小鼠IG基因超突变的分析显示，C至G和G至C的颠换大大减少，这与其脱氧胞苷酰转移酶活性的破坏一致。有趣的是，REV 1AA小鼠也表现出C到T和G到A转换的显著减少。此外，在REV 1AA小鼠中，A：T碱基对处的每种类型的核苷酸取代均匀减少，这与在Polh单倍不足小鼠中观察到的表型相似。这些结果揭示了REV 1在C：G转换和A：T突变的产生中的意想不到的作用，并表明REV 1在超突变过程中通过与其他聚合酶的功能相互作用参与多种诱变途径。免疫学杂志，2009，183：1846-1850.
REV1 is a deoxycytidyl transferase that catalyzes the incorporation of deoxycytidines opposite deoxyguanines and abasic sites. To explore the role of its catalytic activity in Ig gene hypermutation in mammalian cells, we have generated mice expressing a catalytically inactive REV1 (REV1AA). REV1AA mice developed normally and were fertile on a pure C57BL/6 genetic background. B and T cell development and maturation were not affected, and REV1AA B cells underwent normal activation and class switch recombination. Analysis of Ig gene hypermutation in REV1AA mice revealed a great decrease of C to G and G to C transversions, consistent with the disruption of its deoxycytidyl transferase activity. Intriguingly, REV1AA mice also exhibited a significant reduction of C to T and G to A transitions. Moreover, each type of nucleotide substitutions at A:T base pairs was uniformly reduced in REV1AA mice, a phenotype similar to that observed in mice haploinsufficient for Polh. These results reveal an unexpected role for REV1 in the generation of C:G transitions and A:T mutations and suggest that REV1 is involved in multiple mutagenic pathways through functional interaction with other polymerases during the hypermutation process. The Journal of Immunology, 2009,183: 1846-1850.