Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer.
Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer.
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DOI：
10.1093/nar/gkab492
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发表时间：
2021-07-09
影响因子：
14.9
通讯作者：
Yamagata Y
中科院分区：
文献类型：
--
作者：
Nakamura T;Okabe K;Hirayama S;Chirifu M;Ikemizu S;Morioka H;Nakabeppu Y;Yamagata Y
哺乳动物MutY同源物（MUTYH）是一种腺嘌呤DNA糖基化酶，其切除插入相对于8-氧代鸟嘌呤（8-oxoG）的腺嘌呤。已知人类MUTYH基因的遗传变异导致MUTYH相关息肉病（MAP），其与结直肠癌相关。MUTYH参与DNA复制中增殖细胞核抗原（PCNA）的碱基切除修复（BER），这是有效避免突变的独特和关键。另据报道，MUTYH在独特的域间连接子（IDC）区域中具有锌结合基序，该基序在DNA损伤反应中与Rad 9-Rad 1-Hus 1复合物（9-1-1）相互作用，在BER中与脱嘌呤/脱嘧啶核酸内切酶1（APE 1）相互作用。然而，MUTYH及其相互作用蛋白的BER途径的结构基础尚不清楚。在这里，我们确定了小鼠MUTYH和DNA之间的复合物的晶体结构，以及小鼠MUTYH和人PCNA的C-末端结构域之间的复合物的晶体结构。这些结构阐明了A：8-oxoG错配的修复机制，包括涉及MUTYH和PCNA的DNA复制偶联修复过程。锌结合基序被揭示为包括一个组氨酸和三个半胱氨酸残基。IDC，包括锌结合基序，暴露在MUTYH表面，表明其相互作用模式与9-1-1和APE 1，分别。MUTYH的结构解释了MAP突变如何干扰MUTYH功能。
Mammalian MutY homologue (MUTYH) is an adenine DNA glycosylase that excises adenine inserted opposite 8-oxoguanine (8-oxoG). The inherited variations in human MUTYH gene are known to cause MUTYH-associated polyposis (MAP), which is associated with colorectal cancer. MUTYH is involved in base excision repair (BER) with proliferating cell nuclear antigen (PCNA) in DNA replication, which is unique and critical for effective mutation-avoidance. It is also reported that MUTYH has a Zn-binding motif in a unique interdomain connector (IDC) region, which interacts with Rad9–Rad1–Hus1 complex (9–1–1) in DNA damage response, and with apurinic/apyrimidinic endonuclease 1 (APE1) in BER. However, the structural basis for the BER pathway by MUTYH and its interacting proteins is unclear. Here, we determined the crystal structures of complexes between mouse MUTYH and DNA, and between the C-terminal domain of mouse MUTYH and human PCNA. The structures elucidated the repair mechanism for the A:8-oxoG mispair including DNA replication-coupled repair process involving MUTYH and PCNA. The Zn-binding motif was revealed to comprise one histidine and three cysteine residues. The IDC, including the Zn-binding motif, is exposed on the MUTYH surface, suggesting its interaction modes with 9–1–1 and APE1, respectively. The structure of MUTYH explains how MAP mutations perturb MUTYH function.
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影响因子：
14.9
作者：
Ichinoe, A;Behmanesh, M;Nakabeppu, Y
通讯作者：
Nakabeppu, Y
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.8
作者：
Kundu S;Brinkmeyer MK;Livingston AL;David SS
通讯作者：
David SS
影响因子：
64.8
作者：
Fromme, JC;Banerjee, A;Verdine, GL
通讯作者：
Verdine, GL
影响因子：
9.2
作者：
Hayashi, H;Tominaga, Y;Matsumoto, Y
通讯作者：
Matsumoto, Y