Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer
| Autor: | Hiroshi Morioka, Teruya Nakamura, Shogo Hirayama, Shinji Ikemizu, Mami Chirifu, Kohtaro Okabe, Yuriko Yamagata, Yusaku Nakabeppu |
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| Rok vydání: | 2021 |
| Předmět: |
DNA Replication
Models Molecular Guanine DNA Repair DNA damage AcademicSubjects/SCI00010 Amino Acid Motifs 010402 general chemistry medicine.disease_cause 01 natural sciences DNA Glycosylases 03 medical and health sciences Mice MUTYH Structural Biology Proliferating Cell Nuclear Antigen Genetics medicine Animals Humans AP site 030304 developmental biology 0303 health sciences Mutation biology Adenine DNA replication Base excision repair DNA Molecular biology 0104 chemical sciences Proliferating cell nuclear antigen Zinc Adenomatous Polyposis Coli DNA glycosylase biology.protein |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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