The nuclease activity of DNA2 promotes exonuclease 1-independent mismatch repair.
The nuclease activity of DNA2 promotes exonuclease 1-independent mismatch repair.
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DOI：
10.1016/j.jbc.2022.101831
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发表时间：
2022-04
影响因子：
4.8
通讯作者：
Kadyrov, Farid A.
中科院分区：
文献类型：
--
作者：
Kadyrova, Lyudmila Y.;Dahal, Basanta K.;Gujar, Vaibhavi;Daley, James M.;Sung, Patrick;Kadyrov, Farid A.
DNA错配修复(MMR)系统是纠正DNA复制错误的主要DNA修复系统。在真核生物中，MMR系统通过依赖和不依赖于外切核酸酶1(EXO1)的机制发挥作用，EXO1是一种在DNA代谢中具有多种作用的酶。虽然EXO1依赖的MMR的机制已被很好地理解，但对EXO1非依赖的MMR却知之甚少。在这里，我们提供了遗传和生化证据，证明DNA2核酸酶/解旋酶在EXO1非依赖性MMR中发挥作用。用纯化的人类蛋白重组的生化反应表明，DNA 2的核酸酶活性通过涉及DNA聚合酶δ的错配切割无关的机制促进了不依赖于ExO1的MMR反应。我们表明，在DNA 2促进的MMR反应中，DNA聚合酶ε不能取代DNA聚合酶δ。与其核酸酶活性不同，DNA2的解旋酶活性对于蛋白质增强MMR反应的能力是必不可少的。进一步的研究证实，DNA 2通过增加DNA聚合酶δ的链置换活性而参与不依赖于ExO1的MMR反应。这些数据揭示了一种与EXO1无关的失配修复机制。
The DNA mismatch repair (MMR) system is a major DNA repair system that corrects DNA replication errors. In eukaryotes, the MMR system functions via mechanisms both dependent on and independent of exonuclease 1 (EXO1), an enzyme that has multiple roles in DNA metabolism. Although the mechanism of EXO1-dependent MMR is well understood, less is known about EXO1-independent MMR. Here, we provide genetic and biochemical evidence that the DNA2 nuclease/helicase has a role in EXO1-independent MMR. Biochemical reactions reconstituted with purified human proteins demonstrated that the nuclease activity of DNA2 promotes an EXO1-independent MMR reaction via a mismatch excision-independent mechanism that involves DNA polymerase δ. We show that DNA polymerase ε is not able to replace DNA polymerase δ in the DNA2-promoted MMR reaction. Unlike its nuclease activity, the helicase activity of DNA2 is dispensable for the ability of the protein to enhance the MMR reaction. Further examination established that DNA2 acts in the EXO1-independent MMR reaction by increasing the strand-displacement activity of DNA polymerase δ. These data reveal a mechanism for EXO1-independent mismatch repair.
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影响因子：
14.9
作者：
Ganai RA;Zhang XP;Heyer WD;Johansson E
通讯作者：
Johansson E
影响因子：
16
作者：
Ghodgaonkar, Medini Manohar;Lazzaro, Federico;Olivera-Pimentel, Maite;Artola-Boran, Mariela;Cejka, Petr;Reijns, Martin A.;Jackson, Andrew P.;Plevani, Paolo;Muzi-Falconi, Marco;Jiricny, Josef
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Jiricny, Josef
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作者：
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Campbell, JL
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DRUMMOND, JT;LI, GM;MODRICH, P
通讯作者：
MODRICH, P
影响因子：
4.8
作者：
Blanko, Elena Rodriges;Kadyrova, Lyudmila Y.;Kadyrov, Farid A.
通讯作者：
Kadyrov, Farid A.