Artículo
Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans
Dingler, Felix A.; Wang, Meng; Mu, Anfeng; Millington, Christopher L.; Oberbeck, Nina; Watcham, Sam; Pontel, Lucas Blas
; 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.
Fecha de publicación:
12/2020
Editorial:
Cell Press
Revista:
Molecular Cell
ISSN:
1097-2765
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(IBIOBA - MPSP)
Articulos de INST. D/INV.EN BIOMED.DE BS AS-CONICET-INST. PARTNER SOCIEDAD MAX PLANCK
Articulos de INST. D/INV.EN BIOMED.DE BS AS-CONICET-INST. PARTNER SOCIEDAD MAX PLANCK
Citación
Dingler, Felix A.; Wang, Meng; Mu, Anfeng; Millington, Christopher L.; Oberbeck, Nina; et al.; Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans; Cell Press; Molecular Cell; 80; 6; 12-2020; 996-1012.e9
Compartir
Altmétricas