Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans
| Autor: | Etsuro Ito, Seiji Kojima, Kenichi Yoshida, Rui Yu, Camille Nadler, Paul S. Monks, Asuka Hira, Nicola K. Wilson, Motohiro Kato, Ashley N. Kamimae-Lanning, Satoru Miyano, Hiromasa Yabe, Tomoo Osumi, Minako Mori, Miharu Yabe, Michael R. G. Hodskinson, Minoru Takata, Hideki Muramatsu, Lucas B. Pontel, Seishi Ogawa, Toshinori Moriguchi, Christopher L. Millington, Yusuke Okamoto, Masayuki Kobayashi, Yuichi Shiraishi, Meng Wang, Ketan J. Patel, Frederic Langevin, Berthold Göttgens, Yusuke Okuno, Sam Watcham, Felix A. Dingler, Rebecca Cordell, Keitaro Matsuo, Nina Oberbeck, Anfeng Mu |
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| Přispěvatelé: | Wilson, Nicola [0000-0003-0865-7333], Gottgens, Berthold [0000-0001-6302-5705], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
DNA Repair Somatic cell medicine.disease_cause Substrate Specificity purl.org/becyt/ford/1 [https] DNA Adducts Mice 0302 clinical medicine Child IMMUNODEFICIENCY 0303 health sciences Mutation Leukemia Aldehyde Dehydrogenase Mitochondrial CANCER Cell biology Child Preschool Female Stem cell mutagenesis Adolescent DNA repair DNA damage AGEING Biology HEMATOPOIESIS DNA DAMAGE Article 03 medical and health sciences medicine Animals Humans cancer FORMALDEHYDE HEMATOPOIETIC STEM CELLS purl.org/becyt/ford/1.6 [https] Molecular Biology 030304 developmental biology ALDH2 Aldehydes MUTAGENESIS Mutagenesis Alcohol Dehydrogenase Infant ONCOMETABOLITE Cell Biology medicine.disease oncometabolite hematopoiesis hematopoietic stem cells BONE MARROW FAILURE ageing formaldehyde bone marrow failure immunodeficiency 030217 neurology & neurosurgery |
| Zdroj: | Molecular Cell CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| ISSN: | 1097-2765 |
| Popis: | Summary 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. Graphical Abstract Highlights • Toxic levels of genotoxic formaldehyde are produced endogenously in mammals • Two enzymes, ADH5 and ALDH2, are critical for clearance of endogenous formaldehyde • Their loss in mice and humans causes defective hematopoiesis and increased cancer • Elevated formaldehyde causes DNA damage and mutation signature found in many cancers Dingler et al. show that formaldehyde is produced endogenously at sufficient levels to induce and overwhelm DNA repair. Two enzymes, ADH5 and ALDH2, are critical in clearance of formaldehyde, whose loss results in a bone marrow failure and leukemia syndrome of purely metabolic origin. |
| Databáze: | OpenAIRE |
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