The fidelity of DNA replication, particularly on GC-rich templates, is reduced by defects of the Fe-S cluster in DNA polymerase δ.
The fidelity of DNA replication, particularly on GC-rich templates, is reduced by defects of the Fe-S cluster in DNA polymerase δ.
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DOI：
10.1093/nar/gkab371
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发表时间：
2021-06-04
影响因子：
14.9
通讯作者：
Petes TD
中科院分区：
文献类型：
--
作者：
Kiktev DA;Dominska M;Zhang T;Dahl J;Stepchenkova EI;Mieczkowski P;Burgers PM;Lujan S;Burkholder A;Kunkel TA;Petes TD
铁硫簇（4Fe-4S）存在于许多与DNA复制和修复有关的酶中。这些簇对酶活性的贡献尚未完全了解。我们确定了MET 18（MMS 19）基因的酿酒酵母作为一个强大的突变富含GC的基因。Met 18 p是将铁硫簇有效插入各种蛋白质所必需的。met 18突变体在短侧翼重复序列之间具有升高的缺失率，与增加的DNA聚合酶滑移一致。这种表型与在减弱铁-硫簇结合的POL 3（编码Pol δ的催化亚基）突变体中观察到的表型非常相似。可比较的POL 2突变体（Pol β）不增加缺失。对met 18菌株导致Pol δ的DNA合成受损的结论的进一步支持是观察到从met 18菌株分离的Pol δ具有较少的结合铁，并且在体外比野生型全酶具有较少的加工性。
Iron-sulfur clusters (4Fe–4S) exist in many enzymes concerned with DNA replication and repair. The contribution of these clusters to enzymatic activity is not fully understood. We identified the MET18 (MMS19) gene of Saccharomyces cerevisiae as a strong mutator on GC-rich genes. Met18p is required for the efficient insertion of iron-sulfur clusters into various proteins. met18 mutants have an elevated rate of deletions between short flanking repeats, consistent with increased DNA polymerase slippage. This phenotype is very similar to that observed in mutants of POL3 (encoding the catalytic subunit of Pol δ) that weaken binding of the iron-sulfur cluster. Comparable mutants of POL2 (Pol ϵ) do not elevate deletions. Further support for the conclusion that met18 strains result in impaired DNA synthesis by Pol δ are the observations that Pol δ isolated from met18 strains has less bound iron and is less processive in vitro than the wild-type holoenzyme.
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