Kargapolova, Yulia ORCID: 0000-0001-7541-5778, Rehimi, Rizwan, Kayserili, Huelya, Bruehl, Joanna, Sofiadis, Konstantinos, Zirkel, Anne, Palikyras, Spiros, Mizi, Athanasia, Li, Yun, Yigit, Goekhan, Hoischen, Alexander ORCID: 0000-0002-8072-4476, Frank, Stefan, Russ, Nicole, Trautwein, Jonathan, van Bon, Bregje, Gilissen, Christian ORCID: 0000-0003-1693-9699, Laugsch, Magdalena, Gusmao, Eduardo Gade, Josipovic, Natasa ORCID: 0000-0001-7683-0869, Altmueller, Janine, Nuernberg, Peter, Laengst, Gernot, Kaiser, Frank J., Watrin, Erwan, Brunner, Han, Rada-Iglesias, Alvaro ORCID: 0000-0001-7137-1341, Kurian, Leo ORCID: 0000-0001-7466-5169, Wollnik, Bernd ORCID: 0000-0003-2589-0364, Bouazoune, Karim and Papantonis, Argyris (2021). Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology. Nat. Commun., 12 (1). BERLIN: NATURE RESEARCH. ISSN 2041-1723

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Abstract

Members 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kargapolova, YuliaUNSPECIFIEDorcid.org/0000-0001-7541-5778UNSPECIFIED
Rehimi, RizwanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kayserili, HuelyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruehl, JoannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sofiadis, KonstantinosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zirkel, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palikyras, SpirosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mizi, AthanasiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoischen, AlexanderUNSPECIFIEDorcid.org/0000-0002-8072-4476UNSPECIFIED
Frank, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Russ, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trautwein, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Bon, BregjeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gilissen, ChristianUNSPECIFIEDorcid.org/0000-0003-1693-9699UNSPECIFIED
Laugsch, MagdalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gusmao, Eduardo GadeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Josipovic, NatasaUNSPECIFIEDorcid.org/0000-0001-7683-0869UNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laengst, GernotUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaiser, Frank J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Watrin, ErwanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunner, HanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rada-Iglesias, AlvaroUNSPECIFIEDorcid.org/0000-0001-7137-1341UNSPECIFIED
Kurian, LeoUNSPECIFIEDorcid.org/0000-0001-7466-5169UNSPECIFIED
Wollnik, BerndUNSPECIFIEDorcid.org/0000-0003-2589-0364UNSPECIFIED
Bouazoune, KarimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papantonis, ArgyrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-601645
DOI: 10.1038/s41467-021-23327-1
Journal or Publication Title: Nat. Commun.
Volume: 12
Number: 1
Date: 2021
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROTEIN-STRUCTURE; BINDING DOMAIN; CHROMATIN; MUTATIONS; GENE; STRESS; PBAF; TRANSLOCATION; PHENOTYPES; SMARCB1Multiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60164

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