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Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer
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 excisio...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266592/ https://www.ncbi.nlm.nih.gov/pubmed/34142156 http://dx.doi.org/10.1093/nar/gkab492 |
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author | Nakamura, Teruya Okabe, Kohtaro Hirayama, Shogo Chirifu, Mami Ikemizu, Shinji Morioka, Hiroshi Nakabeppu, Yusaku Yamagata, Yuriko |
author_facet | Nakamura, Teruya Okabe, Kohtaro Hirayama, Shogo Chirifu, Mami Ikemizu, Shinji Morioka, Hiroshi Nakabeppu, Yusaku Yamagata, Yuriko |
author_sort | Nakamura, Teruya |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8266592 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-82665922021-07-09 Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer Nakamura, Teruya Okabe, Kohtaro Hirayama, Shogo Chirifu, Mami Ikemizu, Shinji Morioka, Hiroshi Nakabeppu, Yusaku Yamagata, Yuriko Nucleic Acids Res Structural Biology 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. Oxford University Press 2021-06-18 /pmc/articles/PMC8266592/ /pubmed/34142156 http://dx.doi.org/10.1093/nar/gkab492 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Structural Biology Nakamura, Teruya Okabe, Kohtaro Hirayama, Shogo Chirifu, Mami Ikemizu, Shinji Morioka, Hiroshi Nakabeppu, Yusaku Yamagata, Yuriko Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer |
title | Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer |
title_full | Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer |
title_fullStr | Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer |
title_full_unstemmed | Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer |
title_short | Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer |
title_sort | structure of the mammalian adenine dna glycosylase mutyh: insights into the base excision repair pathway and cancer |
topic | Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266592/ https://www.ncbi.nlm.nih.gov/pubmed/34142156 http://dx.doi.org/10.1093/nar/gkab492 |
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