Evidence for preferential mismatch repair of lagging strand DNA replication errors in yeast
Evidence for preferential mismatch repair of lagging strand DNA replication errors in yeast
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DOI：
10.1016/s0960-9822(03)00284-7
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发表时间：
2003-04-29
期刊：
影响因子：
9.2
通讯作者：
Kunkel, TA
中科院分区：
文献类型：
--
作者：
Pavlov, YI;Mian, IM;Kunkel, TA
双链体DNA通过前导链和滞后链模板的协调复制以5 '-3'方向复制，所述前导链和滞后链模板具有稍微不同的蛋白质和机制，提供了两条链复制保真度差异的可能性。我们之前表明，在酿酒酵母中，活性复制起点在DNA中未修复的8-氧代鸟嘌呤（GO）复制导致的碱基置换率中建立了链偏倚[1]。较低的诱变与复制滞后链模板相关。在这里，我们测试的假设，这种偏见是由于更有效地修复滞后的立场错配，通过测量突变率ogg 1菌株的报告等位基因在两个方向上的基因座上的复制起点对侧的染色体III。我们比较了MMR-精通菌株与MMR基因MSH 2、MSH 6、MLH 1或EXOI缺失的菌株。MMR的丧失通过优先增加滞后链复制的诱变来降低链偏倚。我们的结论是，GO-A错配产生的滞后链复制更有效地修复。这与冈崎片段和PCNA的5'端在滞后链复制期间以高密度存在的假设一致，其被用作体内错配修复的链辨别信号。
Duplex DNA is replicated in the 5'-3'direction by coordinated copying of leading and lagging strand templates with somewhat different proteins and mechanics, providing the potential for differences in the fidelity of replication of the two strands. We previously showed that in Saccharomyces cerevisiae, active replication origins establish a strand bias in the rate of base substitutions resulting from replication of unrepaired 8-oxo-guanine (GO) in DNA [1]. Lower mutagenesis was associated with replicating lagging strand templates. Here, we test the hypothesis that this bias is due to more efficient repair of lagging stand mismatches by measuring mutation rates in ogg1 strains with a reporter allele in two orientations at loci on opposite sides of a replication origin on chromosome Ill. We compare a MMR-proficient strain to strains deleted for the MMR genes MSH2, MSH6, MLH1, or EXOI. Loss of MMR reduces the strand bias by preferentially increasing mutagenesis for lagging strand replication. We conclude that GO-A mismatches generated during lagging strand replication are more efficiently repaired. This is consistent with the hypothesis that 5' ends of Okazaki fragments and PCNA, present at high density during lagging strand replication, are used as strand discrimination signals for mismatch repair in vivo.