Frameshift mutagenesis and microsatellite instability induced by human alkyladenine DNA glycosylase.
Frameshift mutagenesis and microsatellite instability induced by human alkyladenine DNA glycosylase.
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DOI：
10.1016/j.molcel.2010.01.038
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发表时间：
2010-03-26
期刊：
影响因子：
16
通讯作者：
Samson LD
中科院分区：
文献类型：
--
作者：
Klapacz J;Lingaraju GM;Guo HH;Shah D;Moar-Shoshani A;Loeb LA;Samson LD
人烷基腺嘌呤DNA糖基化酶（hAAG）从DNA中去除烷基化嘌呤、次黄嘌呤和乙二基，形成碱基（AP）位点。令人惊讶的是，hAAG的高表达增加了自发移码突变。通过随机诱变8个活性位点残基，我们分离到hAAG- y127i /H136L双突变体，该突变体诱导的移码突变率高于野生型hAAG；Y127I突变占hAAG-Y127I/H136L诱导突变表型的大部分。hAAG-Y127I/H136L和hAAG-Y127I突变体在酿酒葡萄球菌中增加了高达120倍的自发帧移率，并且还在人类细胞中诱导了高速率的微卫星不稳定性（MSI）。hAAG及其突变体结合含有1和2碱基对环的DNA具有显著的亲和力，从而屏蔽了它们的错配修复；这种结合的强度与它们诱导突变表型的能力相关。这项研究为haag诱导的基因组不稳定性的机制提供了重要的见解。
Human alkyladenine DNA glycosylase (hAAG) excises alkylated purines, hypoxanthine and etheno bases from DNA to form abasic (AP) sites. Surprisingly, elevated expression of hAAG increases spontaneous frameshift mutagenesis. By random mutagenesis of eight active site residues, we isolated hAAG-Y127I/H136L double mutant that induces even higher rates of frameshift mutation than the wild-type hAAG; the Y127I mutation accounts for the majority of the hAAG-Y127I/H136L induced mutator phenotype. The hAAG-Y127I/H136L and hAAG-Y127I mutants increased the rate of spontaneous frameshifts by up to 120-fold in S. cerevisiae, and also induced high rates of microsatellite instability (MSI) in human cells. hAAG and its mutants bind DNA containing 1 and 2 base pair-loops with significant affinity, thus shielding them from mismatch repair; the strength of such binding correlates with their ability to induce the mutator phenotype. This study provides important insights into the mechanism of hAAG-induced genomic instability.
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影响因子：
3.2
作者：
CHEN, BRJ;CARROLL, P;SAMSON, L
通讯作者：
SAMSON, L
影响因子：
3.8
作者：
Chen, Cheng-Yao;Guo, Haiwei H.;Loeb, Lawrence A.
通讯作者：
Loeb, Lawrence A.
DOI：
10.1073/pnas.0505949102
发表时间：
2005-12-20
影响因子：
11.1
作者：
Garg, P;Burgers, PM
通讯作者：
Burgers, PM
影响因子：
4.8
作者：
Bebenek, K;Garcia-Diaz, M;Kunkel, TA
通讯作者：
Kunkel, TA
DOI：
10.1016/0027-5107(95)00064-p
发表时间：
1995-09-01
影响因子：
2.3
作者：
KALINOWSKI, DP;LARIMER, FW;PLEWA, MJ
通讯作者：
PLEWA, MJ