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

• Nakamura, Teruya

  Graduate School of Pharmaceutical Sciences, Kumamoto University Priority Organization for Innovation and Excellence, Kumamoto University

• Okabe, Kohtaro

  Graduate School of Pharmaceutical Sciences, Kumamoto University

• Hirayama, Shogo

  Graduate School of Pharmaceutical Sciences, Kumamoto University

• Chirifu, Mami

  Graduate School of Pharmaceutical Sciences, Kumamoto University

• Ikemizu, Shinji

  Graduate School of Pharmaceutical Sciences, Kumamoto University

• Morioka, Hiroshi

  Graduate School of Pharmaceutical Sciences, Kumamoto University

• Nakabeppu, Yusaku

  Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University

• Yamagata, Yuriko

  Graduate School of Pharmaceutical Sciences, Kumamoto University Shokei University and Shokei University Junior College

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 mutationavoidance. 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 mouseMUTYH 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.

Journal

• Nucleic Acids Research

  Nucleic Acids Research 49 (12), 7154-7163, 2021-07-09

  Oxford University Press

Keywords

• Genetics

Details

• CRID: 1050298532704135808
• NII Article ID: 120007119905
• NII Book ID: AA00760269
• DOI: 10.1093/nar/gkab492
• ISSN: 13624962
• ISSN: 03051048
• HANDLE: 2324/4482102
• Web Site: http://academic.oup.com/nar/article-pdf/49/12/7154/38885718/gkab492.pdf
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN