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Title: Protein kinase A inhibits tumor mutator APOBEC3B through phosphorylation
Authors: Matsumoto, Tadahiko
Shirakawa, Kotaro
Yokoyama, Masaru
Fukuda, Hirofumi
Sarca, Anamaria Daniela
Koyabu, Sukenao
Yamazaki, Hiroyuki
Kazuma, Yasuhiro
Matsui, Hiroyuki
Maruyama, Wataru
Nagata, Kayoko
Tanabe, Fumiko
Kobayashi, Masayuki
Shindo, Keisuke
Morishita, Ryo
Sato, Hironori
Takaori-Kondo, Akifumi
Author's alias: 松本, 忠彦
白川, 康太郎
横山, 勝
福田, 寛文
サルカ, アナマリア ダニエラ
小藪, 助直
山崎, 寛章
数馬, 安浩
松井, 宏行
丸山, 亙
永田, 佳代子
田邊, 史子
小林, 正行
新堂, 啓祐
森下, 了
佐藤, 裕徳
髙折, 晃史
Keywords: Oncogenes
Phosphorylation
Issue Date: 5-Jun-2019
Publisher: Springer Science and Business Media LLC
Journal title: Scientific Reports
Volume: 9
Thesis number: 8307
Abstract: APOBEC3B cytidine deaminase (A3B) catalyzes cytosine into uracil in single-strand DNA and induces C-to-T mutations in genomic DNA of various types of tumors. Accumulation of APOBEC signature mutations is correlated with a worse prognosis for patients with breast cancer or multiple myeloma, suggesting that A3B activity might be a cause of the unfavorable DNA mutations and clonal evolution in these tumors. Phosphorylation of conserved threonine residues of other cytidine deaminases, activation induced deaminase (AID) and APOBEC3G, inhibits their activity. Here we show that protein kinase A (PKA) physically binds to A3B and phosphorylates Thr214. In vitro deaminase assays and foreign DNA editing assays in cells confirm that phosphomimetic A3B mutants, T214D and T214E, completely lose deaminase activity. Molecular dynamics simulation of A3B phosphorylation reveals that Thr214 phosphorylation disrupts binding between the phospho-A3B catalytic core and ssDNA. These mutants still inhibit retroviral infectivity at least partially, and also retain full anti-retrotransposition activity. These results imply that PKA-mediated phosphorylation inhibits A3B mutagenic activity without destructing its innate immune functions. Therefore, PKA activation could reduce further accumulation of mutations in A3B overexpressing tumors.
Description: がんに遺伝子変異を導入する酵素の分子スイッチを発見 --リン酸化によるDNAシトシン脱アミノ化酵素の活性制御機構--. 京都大学プレスリリース. 2019-06-07.
Rights: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
URI: http://hdl.handle.net/2433/241722
DOI(Published Version): 10.1038/s41598-019-44407-9
PubMed ID: 31165764
Related Link: https://www.kyoto-u.ac.jp/ja/research-news/2019-06-07
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