DNA damage alters DNA polymerase delta to a form that exhibits increased discrimination against modified template bases and mismatched primers.
DNA damage alters DNA polymerase delta to a form that exhibits increased discrimination against modified template bases and mismatched primers.
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DOI：
10.1093/nar/gkn1000
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发表时间：
2009-02
影响因子：
14.9
通讯作者：
Lee MY
中科院分区：
文献类型：
--
作者：
Meng X;Zhou Y;Zhang S;Lee EY;Frick DN;Lee MY
人类DNA聚合酶δ (Pol δ4)是由p125、p50、p68和p12亚基组成的异源四聚体，是染色体复制的关键酶。基因毒性物质如紫外线和烷基化化学物质引发DNA损伤反应，其中Pol δ4通过降解p12转化为三聚体（Pol δ3）。我们发现Pol δ3改变了酶的性质：它在含有碱基损伤（O6-MeG, 8-oxoG，一个碱基位点或胸腺嘧啶二聚体）的模板上进行翻译合成的能力较差；更大的校对活动；外切酶/聚合酶活性比增加；错误核苷酸插入和不匹配引物延伸的趋势降低。总的来说，我们的研究结果表明，Pol δ3对引物和模板的错误检测能力比其母体酶强。这些Pol δ3的变化表明，p12在Pol δ4的催化功能中起主要作用，并为细胞对DNA损伤的反应中Pol δ4转化为Pol δ3的基本原理提供了重要的见解。
Human DNA polymerase δ (Pol δ4), a key enzyme in chromosomal replication, is a heterotetramer composed of the p125, p50, p68 and p12 subunits. Genotoxic agents such as UV and alkylating chemicals trigger a DNA damage response in which Pol δ4 is converted to a trimer (Pol δ3) by degradation of p12. We show that Pol δ3 has altered enzymatic properties: it is less able to perform translesion synthesis on templates containing base lesions (O6-MeG, 8-oxoG, an abasic site or a thymine-thymine dimer); a greater proofreading activity; an increased exonuclease/polymerase activity ratio; a decreased tendency for the insertion of wrong nucleotides, and for the extension of mismatched primers. Overall, our findings indicate that Pol δ3 exhibits an enhanced ability for the detection of errors in both primers and templates over its parent enzyme. These alterations in Pol δ3 show that p12 plays a major role in Pol δ4 catalytic functions, and provides significant insights into the rationale for the conversion of Pol δ4 to Pol δ3 in the cellular response to DNA damage.
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影响因子：
3.8
作者：
Lehmann, Alan R.;Niimi, Atsuko;Green, Catherine M.
通讯作者：
Green, Catherine M.
影响因子：
4.8
作者：
Choi, Jeong-Yun;Chowdhury, Goutam;Guengerich, F. Peter
通讯作者：
Guengerich, F. Peter
影响因子：
14.9
作者：
McCulloch, SD;Kokoska, RJ;Kunkel, TA
通讯作者：
Kunkel, TA
DOI：
10.1073/pnas.232340999
发表时间：
2002-11-26
影响因子：
11.1
作者：
Goldsby, RE;Hays, LE;Preston, BD
通讯作者：
Preston, BD
影响因子：
4.8
作者：
Einolf, HJ;Guengerich, FP
通讯作者：
Guengerich, FP