Genetic evidence that both dNTP-stabilized and strand slippage mechanisms may dictate DNA polymerase errors within mononucleotide microsatellites

被引:10
作者
Baptiste, Beverly A.
Jacob, Kimberly D.
Eckert, Kristin A. [1 ]
机构
[1] Penn State Univ, Jake Gittlen Labs Canc Res, Coll Med, Hershey, PA 17033 USA
基金
美国国家卫生研究院;
关键词
Microsatellite; Mutation bias; DNA polymerase fidelity; DNA misalignment; Strand slippage; indel mutation; Mononucleotide; SIMPLE SEQUENCE REPEATS; IN-VITRO; SACCHAROMYCES-CEREVISIAE; TRANSLESION SYNTHESIS; BASE SUBSTITUTION; MUTATION ASSAY; LESION-BYPASS; HINGE REGION; HUMAN CANCER; BETA;
D O I
10.1016/j.dnarep.2015.02.016
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Mononucleotide microsatellites are tandem repeats of a single base pair, abundant within coding exons and frequent sites of mutation in the human genome. Because the repeated unit is one base pair, multiple mechanisms of insertion/deletion (indel) mutagenesis are possible, including strand-slippage, dNTP-stabilized, and misincorportion-misalignment. Here, we examine the effects of polymerase identity (mammalian Pols alpha, beta, kappa, and eta), template sequence, dNTP pool size, and reaction temperature on indel errors during in vitro synthesis of mononucleotide microsatellites. We utilized the ratio of insertion to deletion errors as a genetic indicator of mechanism. Strikingly, we observed a statistically significant bias toward deletion errors within mononucleotide repeats for the majority of the 28 DNA template and polymerase combinations examined, with notable exceptions based on sequence and polymerase identity. Using mutator forms of Pol beta did not substantially alter the error specificity, suggesting that mispairing-misalignment mechanism is not a primary mechanism. Based on our results for mammalian DNA polymerases representing three structurally distinct families, we suggest that dNTP-stabilized mutagenesis may be an alternative mechanism for mononucleotide microsatellite indel mutation. The change from a predominantly dNTP-stabilized mechanism to a strand-slippage mechanism with increasing microsatellite length may account for the differential rates of tandem repeat mutation that are observed genome-wide. (C) 2015 Elsevier B.V. All rights reserved.
引用
收藏
页码:91 / 100
页数:10
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