Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans.
Adolescent
Alcohol Dehydrogenase
/ genetics
Aldehyde Dehydrogenase, Mitochondrial
/ genetics
Aldehydes
/ blood
Animals
Child
Child, Preschool
DNA Adducts
/ genetics
DNA Damage
/ drug effects
DNA Repair
/ drug effects
Female
Formaldehyde
/ blood
Hematopoiesis
/ genetics
Hematopoietic Stem Cells
/ metabolism
Humans
Infant
Leukemia
/ blood
Male
Mice
Mutation
/ genetics
Substrate Specificity
DNA damage
ageing
bone marrow failure
cancer
formaldehyde
hematopoiesis
hematopoietic stem cells
immunodeficiency
mutagenesis
oncometabolite
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
17 12 2020
17 12 2020
Historique:
received:
15
06
2020
revised:
20
08
2020
accepted:
08
10
2020
pubmed:
5
11
2020
medline:
16
1
2021
entrez:
4
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33147438
pii: S1097-2765(20)30719-X
doi: 10.1016/j.molcel.2020.10.012
pmc: PMC7758861
pii:
doi:
Substances chimiques
Aldehydes
0
DNA Adducts
0
Formaldehyde
1HG84L3525
Adh5 protein, mouse
EC 1.1.1.1
Alcohol Dehydrogenase
EC 1.1.1.1
Aldehyde Dehydrogenase, Mitochondrial
EC 1.2.1.3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
996-1012.e9Subventions
Organisme : Medical Research Council
ID : MC_PC_17230
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_12009
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00016/17
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0902418
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U105178811
Pays : United Kingdom
Organisme : NIEHS NIH HHS
ID : P30 ES010126
Pays : United States
Organisme : Cancer Research UK
ID : C60150/A23919
Pays : United Kingdom
Organisme : NIEHS NIH HHS
ID : P42 ES005948
Pays : United States
Organisme : Medical Research Council
ID : MR/M008975/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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