The mismatch repair endonuclease MutLα tethers duplex regions of DNA together and relieves DNA torsional tension.
The mismatch repair endonuclease MutLα tethers duplex regions of DNA together and relieves DNA torsional tension.
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DOI：
10.1093/nar/gkad096
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发表时间：
2023-04-11
影响因子：
14.9
通讯作者：
Manhart CM
中科院分区：
文献类型：
--
作者：
Witte SJ;Rosa IM;Collingwood BW;Piscitelli JM;Manhart CM
在真核错配修复中，MutS 同源物识别错配并招募 MutLα 核酸内切酶，该酶在新复制的、含有错误的 DNA 链中引入切口。切口是由于错配而产生的，但其位点远达数百个碱基对。 MutLα 切口可通过核酸外切酶 (Exo1) 促进错配切除，或通过 DNA 聚合酶的链置换活性去除错配，DNA 聚合酶可与活瓣核酸内切酶结合使用。模型表明 MutL 同源核酸内切酶形成寡聚复合物，促进链捕获机制并被链捕获机制激活，尽管此类模型从未经过明确测试。我们提供的证据表明，错配修复 MutLα 核酸内切酶是由 DNA-DNA 关联激活的，并且它可以利用这一特性来克服 DNA 扭转障碍。通过 DNA 连接和下拉实验，我们确定 MutLα 核酸内切酶关联两个 DNA 双链体。通过核酸酶检测，我们确定这种活性会刺激 MutLα 的核酸内切酶功能。我们还观察到 MutLα 增强了拓扑异构酶，而不会在 DNA 本身上产生切口。我们的数据为 MutL 蛋白在错配修复过程中如何与 DNA 相互作用，以及 MutL 同源物如何参与其他过程（例如重组和三核苷酸重复扩增）提供了机制解释。
In eukaryotic mismatch repair, MutS homologs recognize mismatches and recruit the MutLα endonuclease which introduces a nick in the newly replicated, error-containing DNA strand. The nick occurs in response to the mismatch, but at a site up to several hundred base pairs away. The MutLα nick promotes mismatch excision by an exonuclease (Exo1) or removal by the strand displacement activity of a DNA polymerase which may work in conjunction with a flap endonuclease. Models have suggested that MutL homolog endonucleases form oligomeric complexes which facilitate and are activated by strand capture mechanisms, although such models have never been explicitly tested. We present evidence that the mismatch repair MutLα endonuclease is activated by DNA–DNA associations and that it can use this property to overcome DNA torsional barriers. Using DNA ligation and pull-down experiments, we determined that the MutLα endonuclease associates two DNA duplexes. Using nuclease assays, we determined that this activity stimulates MutLα’s endonuclease function. We also observe that MutLα enhances a topoisomerase without nicking the DNA itself. Our data provide a mechanistic explanation for how MutL proteins interact with DNA during mismatch repair, and how MutL homologs participate in other processes, such as recombination and trinucleotide repeat expansions.
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DOI：
10.1073/pnas.1918517117
发表时间：
2020-07-28
影响因子：
11.1
作者：
Hao, Pengyu;LeBlanc, Sharonda J.;Weninger, Keith R.
通讯作者：
Weninger, Keith R.
影响因子：
14.9
作者：
Hermans N;Laffeber C;Cristovão M;Artola-Borán M;Mardenborough Y;Ikpa P;Jaddoe A;Winterwerp HH;Wyman C;Jiricny J;Kanaar R;Friedhoff P;Lebbink JH
通讯作者：
Lebbink JH
影响因子：
14.9
作者：
Elez M;Radman M;Matic I
通讯作者：
Matic I
DOI：
10.1002/yea.3512
发表时间：
2021-01
期刊：
Yeast (Chichester, England)
影响因子：
--
作者：
Furman CM;Elbashir R;Alani E
通讯作者：
Alani E
影响因子：
3.3
作者：
Cooper, MP;Balajee, AS;Bohr, VA
通讯作者：
Bohr, VA