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j.molcel.2020.10.012.pdf | 6.05 MB | Adobe PDF | 見る/開く |
タイトル: | Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans |
著者: | Dingler, Felix A. Wang, Meng Mu, Anfeng Millington, Christopher L. Oberbeck, Nina Watcham, Sam Pontel, Lucas B. Kamimae-Lanning, Ashley N. Langevin, Frederic Nadler, Camille Cordell, Rebecca L. Monks, Paul S. Yu, Rui Wilson, Nicola K. Hira, Asuka Yoshida, Kenichi Mori, Minako Okamoto, Yusuke Okuno, Yusuke Muramatsu, Hideki Shiraishi, Yuichi Kobayashi, Masayuki Moriguchi, Toshinori Osumi, Tomoo Kato, Motohiro Miyano, Satoru Ito, Etsuro Kojima, Seiji Yabe, Hiromasa Yabe, Miharu Matsuo, Keitaro Ogawa, Seishi Göttgens, Berthold Hodskinson, Michael R.G. Takata, Minoru Patel, Ketan J. |
著者名の別形: | 牟, 安峰 平, 明日香 吉田, 健一 森, 美奈子 岡本, 裕介 奥野, 友介 村松, 秀城 白石, 友一 小林, 正行 森口, 寿徳 大隅, 朋生 加藤, 元博 宮野, 悟 伊藤, 悦朗 小島, 勢二 矢部, 普正 矢部, みはる 松尾, 恵太郎 小川, 誠司 髙田, 穣 |
キーワード: | hematopoietic stem cells hematopoiesis bone marrow failure immunodeficiency formaldehyde oncometabolite ageing DNA damage mutagenesis cancer |
発行日: | 17-Dec-2020 |
出版者: | Elsevier BV |
誌名: | Molecular Cell |
巻: | 80 |
号: | 6 |
開始ページ: | 996 |
終了ページ: | 1012.e9 |
抄録: | Reactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues. |
記述: | 新規の遺伝性再⽣不良性貧⾎症「ADH5/ALDH2 ⽋損症」を発⾒ --⽇本⼈半数が持つお酒が飲めない体質遺伝⼦と遺伝性⾎液難病の関連性--. 京都大学プレスリリース. 2020-11-06. |
著作権等: | © 2020 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
URI: | http://hdl.handle.net/2433/255881 |
DOI(出版社版): | 10.1016/j.molcel.2020.10.012 |
PubMed ID: | 33147438 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2020-11-06 |
出現コレクション: | 学術雑誌掲載論文等 |

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