Structure of the mammalian adenine DNA glycosylase MUTYH: Insights into the base excision repair pathway and cancer

Teruya Nakamura, Kohtaro Okabe, Shogo Hirayama, Mami Chirifu, Shinji Ikemizu, Hiroshi Morioka, Yusaku Nakabeppu, Yuriko Yamagata

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7154-7163
Number of pages10
JournalNucleic acids research
Volume49
Issue number12
DOIs
Publication statusPublished - Jul 9 2021

All Science Journal Classification (ASJC) codes

  • Genetics

Fingerprint

Dive into the research topics of 'Structure of the mammalian adenine DNA glycosylase MUTYH: Insights into the base excision repair pathway and cancer'. Together they form a unique fingerprint.

Cite this