Show simple item record

dc.contributor.authorDingler, Felix Aen
dc.contributor.authorWang, Mengen
dc.contributor.authorMu, Anfengen
dc.contributor.authorMillington, Christopher Len
dc.contributor.authorOberbeck, Ninaen
dc.contributor.authorWatcham, Samen
dc.contributor.authorPontel, Lucas Ben
dc.contributor.authorKamimae-Lanning, Ashley Nen
dc.contributor.authorLangevin, Fredericen
dc.contributor.authorNadler, Camilleen
dc.contributor.authorCordell, Rebecca Len
dc.contributor.authorMonks, Paul Sen
dc.contributor.authorYu, Ruien
dc.contributor.authorWilson, Nicolaen
dc.contributor.authorHira, Asukaen
dc.contributor.authorYoshida, Kenichien
dc.contributor.authorMori, Minakoen
dc.contributor.authorOkamoto, Yusukeen
dc.contributor.authorOkuno, Yusukeen
dc.contributor.authorMuramatsu, Hidekien
dc.contributor.authorShiraishi, Yuichien
dc.contributor.authorKobayashi, Masayukien
dc.contributor.authorMoriguchi, Toshinorien
dc.contributor.authorOsumi, Tomooen
dc.contributor.authorKato, Motohiroen
dc.contributor.authorMiyano, Satoruen
dc.contributor.authorIto, Etsuroen
dc.contributor.authorKojima, Seijien
dc.contributor.authorYabe, Hiromasaen
dc.contributor.authorYabe, Miharuen
dc.contributor.authorMatsuo, Keitaroen
dc.contributor.authorOgawa, Seishien
dc.contributor.authorGottgens, Bertholden
dc.contributor.authorHodskinson, Michael RGen
dc.contributor.authorTakata, Minoruen
dc.contributor.authorPatel, Ketan Jen
dc.date.accessioned2020-11-07T00:30:11Z
dc.date.available2020-11-07T00:30:11Z
dc.date.issued2020-11-04en
dc.identifier.issn1097-2765
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/312524
dc.description.abstractReactive 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.
dc.languageengen
dc.publisherCell Press
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleTwo Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans.en
dc.typeArticle
prism.publicationDate2020en
prism.publicationNameMolecular Cellen
dc.identifier.doi10.17863/CAM.59621
dcterms.dateAccepted2020-10-08en
rioxxterms.versionofrecord10.1016/j.molcel.2020.10.012en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2020-11-04en
dc.contributor.orcidWilson, Nicola [0000-0003-0865-7333]
dc.contributor.orcidGottgens, Berthold [0000-0001-6302-5705]
dc.identifier.eissn1097-4164
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idMEDICAL RESEARCH COUNCIL (MR/M008975/1)
pubs.funder-project-idMedical Research Council (MC_PC_17230)
cam.issuedOnline2020-11-03en


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International