Atomic-level, 3-D structure of MUTYH protein opens small window into DNA repair mechanism

Date:
August 2, 2021
Source:
Kumamoto University
Summary:
A research team has analyzed the three-dimensional structure of a
protein that suppresses the development of colorectal polyposis,
MUTYH, at the atomic level and clarified the repair mechanism for
DNA mispairings.

Since mutations in the MUTYH gene cause heritable colorectal
polyposis, which leads to colorectal cancer, the researchers expect
that this work will be useful for future research on heritable
colorectal polyposis associated with MUTYH.



FULL STORY ========================================================================== Researchers have analyzed the three-dimensional structure of a protein
that suppresses the development of colorectal polyposis, MUTYH, at the
atomic level and clarified the repair mechanism for DNA mispairings
by MUTYH. Since mutations in the MUTYH gene cause heritable colorectal polyposis, which leads to colorectal cancer, the researchers expect that
this work will be useful for future research on heritable colorectal
polyposis associated with MUTYH.


========================================================================== Reactive oxygen species produced inside cells oxidize DNA, and when
the guanine base in DNA undergoes oxidation, 8-oxoguanine base is
produced. Normally, guanine pairs with cytosine, but 8-oxoguanine also
pairs with adenine, causing mutations that can lead to cancer and other aging-related diseases.

MUTYH is a protein that finds and removes adenine that has been mispaired
with 8-oxoguanine. Mutations in its gene are known to cause heritable colorectal polyposis which can lead to colorectal cancer. Furthermore,
the repair efficiency of MUTYH increases when it interacts with PCNA,
a protein involved in DNA replication, but the repair mechanisms at the
atomic level have not been clarified.

To accurately understand the function of a protein, it is important
to know its structure at the atomic level. X-ray crystallography is
a method that allows us to observe the molecules of living organisms
at a scale of 1 x 10-10 m. Using this method, a research group led by
Kumamoto University (Japan) has determined the X-ray crystal structure
of MUTYH bound to a mispairing in DNA and the X-ray crystal structure
of MUTYH bound to PCNA. Their analysis showed how MUTYH binds to the
DNA double helix and searches for adenine:8-oxoguanine mispairings in
DNA. Based on the three-dimensional structures of PCNA and MUTYH, the researchers proposed that PCNA serves as a clamp on the DNA double helix
and recruits MUTYH to the mispair site, which would clarify the mechanism
by which MUTYH and PCNA cooperate to repair DNA. Furthermore, analysis
of the 3D structure of MUTYH and DNA showed that mutations in the MUTYH
gene reduce the binding affinity of MUTYH to DNA and destabilize the 3D structure of MUTYH, which leads to a decrease of its DNA repair activity.

"Since MUTYH and PCNA are known to work with various proteins involved in
DNA repair, the three-dimensional structures that we clarified in this
study should serve as a basis for further understanding the DNA repair mechanisms centered around MUTYH and PCNA," said Associate Professor
Teruya Nakamura, who led the study. "We expect that the clarification
of their atomic-level structures will be useful for future studies of
heritable colorectal polyposis associated with MUTYH." This research
was posted online in Nucleic Acids Research on 18 June 2021.

========================================================================== Story Source: Materials provided by Kumamoto_University. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Teruya Nakamura, Kohtaro Okabe, Shogo Hirayama, Mami Chirifu, Shinji
Ikemizu, Hiroshi Morioka, Yusaku Nakabeppu, Yuriko
Yamagata. Structure of the mammalian adenine DNA glycosylase MUTYH:
insights into the base excision repair pathway and cancer. Nucleic
Acids Research, 2021; 49 (12): 7154 DOI: 10.1093/nar/gkab492 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210802114951.htm

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