Publication:
Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

dc.contributor.coauthorKargapolova, Yulia
dc.contributor.coauthorRehimi, Rizwan
dc.contributor.coauthorBruehl, Joanna
dc.contributor.coauthorSofiadis, Konstantinos
dc.contributor.coauthorZirkel, Anne
dc.contributor.coauthorPalikyras, Spiros
dc.contributor.coauthorMizi, Athanasia
dc.contributor.coauthorLi, Yun
dc.contributor.coauthorYigit, Gokhan
dc.contributor.coauthorHoischen, Alexander
dc.contributor.coauthorFrank, Stefan
dc.contributor.coauthorRuss, Nicole
dc.contributor.coauthorTrautwein, Jonathan
dc.contributor.coauthorvan Bon, Bregje
dc.contributor.coauthorGilissen, Christian
dc.contributor.coauthorLaugsch, Magdalena
dc.contributor.coauthorGusmao, Eduardo Gade
dc.contributor.coauthorJosipovic, Natasa
dc.contributor.coauthorAltmueller, Janine
dc.contributor.coauthorNuernberg, Peter
dc.contributor.coauthorLaengst, Gernot
dc.contributor.coauthorKaiser, Frank J.
dc.contributor.coauthorWatrin, Erwan
dc.contributor.coauthorBrunner, Han
dc.contributor.coauthorRada-Iglesias, Alvaro
dc.contributor.coauthorKurian, Leo
dc.contributor.coauthorWollnik, Bernd
dc.contributor.coauthorBouazoune, Karim
dc.contributor.coauthorPapantonis, Argyris
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorKayserili, Hülya
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2024-11-09T12:11:56Z
dc.date.issued2021
dc.description.abstractMembers of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance. Members of the CHD chromatin remodeler family are implicated in human pathologies, however CHD6 remained poorly studied. Here, the authors show that CHD6 binds to and regulates autophagy and stress response genes across cell types. They identify a clinical mutation that affects its ability to recruit cofactors, leading to impaired autophagy induction and DNA repair.
dc.description.fulltextYES
dc.description.indexedbyWOS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.openaccessYES
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.sponsorshipUKGM
dc.description.sponsorshipDeutsche Forschungsgemeinschaft TRR81 (Project)
dc.description.sponsorshipCCRC2407
dc.description.sponsorshipElse-Kroener-Fresenius-Stiftung “Key-Project” Grant
dc.description.sponsorshipTRR259
dc.description.sponsorshipInternational Max Planck Research School for Genome Science
dc.description.sponsorshipProjekt DEAL
dc.description.versionPublisher version
dc.description.volume12
dc.identifier.doi10.1038/s41467-021-23327-1
dc.identifier.embargoNO
dc.identifier.filenameinventorynoIR02946
dc.identifier.issn2041-1723
dc.identifier.quartileQ1
dc.identifier.scopus2-s2.0-85106573314
dc.identifier.urihttps://doi.org/10.1038/s41467-021-23327-1
dc.identifier.wos658765200011
dc.keywordsProtein structure
dc.keywordsBinding domain
dc.keywordsChromatin
dc.keywordsMutations
dc.keywordsGene
dc.keywordsStress
dc.keywordsPBAF
dc.keywordsTranslocation
dc.keywordsPhenotypes
dc.keywordsSMARCB1
dc.language.isoeng
dc.publisherNature Publishing Group (NPG)
dc.relation.grantno5/2016
dc.relation.grantno109546710
dc.relation.grantno360043781
dc.relation.grantno2015_A125
dc.relation.grantno397484323
dc.relation.ispartofNature Communications
dc.relation.urihttp://cdm21054.contentdm.oclc.org/cdm/ref/collection/IR/id/9593
dc.subjectScience and technology
dc.titleOverarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorKayserili, Hülya
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit2School of Medicine
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