Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools.
Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools.
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DOI：
10.1093/nar/gkq829
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发表时间：
2011-03
影响因子：
14.9
通讯作者：
Chabes A
中科院分区：
文献类型：
--
作者：
Kumar D;Abdulovic AL;Viberg J;Nilsson AK;Kunkel TA;Chabes A
不平衡的dNTPs诱导突变的机制已经在试管中得到了很好的表征，但在体内却没有。我们已经研究了dNTP失衡导致核糖核苷酸还原酶大亚基Rnr1中不同氨基酸取代的酿酒酵母菌株基因组不稳定的机制。这些菌株具有不同的dNTP失衡，这与CAN1突变率升高有关，替换率和插入-删除率都增加了10至300倍。dTTP和dCTP升高的菌株的突变位置与dATP和dGTP升高的菌株完全不同。因此，不平衡的dNTPs以高度依赖于不平衡的性质和程度的方式降低了基因组的稳定性。尽管校正和错配修复的可用性增强了诱变。这些突变可以解释为不平衡的dntp诱导的误插入，链错位和错配延伸的增加，以牺牲校对为代价。这意味着在提取物中测量的相对dNTP浓度确实可用于体内的复制叉。在一个rnr1菌株中观察到一个有趣的突变链偏倚，这表明s期检查点选择性地阻止了前导链复制过程中的复制错误。
The mechanisms by which imbalanced dNTPs induce mutations have been well characterized within a test tube, but not in vivo. We have examined mechanisms by which dNTP imbalances induce genome instability in strains of Saccharomyces cerevisiae with different amino acid substitutions in Rnr1, the large subunit of ribonucleotide reductase. These strains have different dNTP imbalances that correlate with elevated CAN1 mutation rates, with both substitution and insertion–deletion rates increasing by 10- to 300-fold. The locations of the mutations in a strain with elevated dTTP and dCTP are completely different from those in a strain with elevated dATP and dGTP. Thus, imbalanced dNTPs reduce genome stability in a manner that is highly dependent on the nature and degree of the imbalance. Mutagenesis is enhanced despite the availability of proofreading and mismatch repair. The mutations can be explained by imbalanced dNTP-induced increases in misinsertion, strand misalignment and mismatch extension at the expense of proofreading. This implies that the relative dNTP concentrations measured in extracts are truly available to a replication fork in vivo. An interesting mutational strand bias is observed in one rnr1 strain, suggesting that the S-phase checkpoint selectively prevents replication errors during leading strand replication.
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影响因子：
10.5
作者：
ELLEDGE, SJ;DAVIS, RW
通讯作者：
DAVIS, RW
影响因子：
14.9
作者：
Kumar D;Viberg J;Nilsson AK;Chabes A
通讯作者：
Chabes A
DOI：
10.1007/bf00273611
发表时间：
1991-04-01
期刊：
MOLECULAR & GENERAL GENETICS
影响因子：
--
作者：
JI, JP;MATHEWS, CK
通讯作者：
MATHEWS, CK
DOI：
10.1073/pnas.89.7.2829
发表时间：
1992-04-01
影响因子：
11.1
作者：
KRESNAK, MT;DAVIDSON, RL
通讯作者：
DAVIDSON, RL
影响因子：
5.7
作者：
Eriksson, M;Uhlin, U;Eklund, H
通讯作者：
Eklund, H