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

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Item Type:Article
Title:Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology
Creators Name:Kargapolova, Y. and Rehimi, R. and Kayserili, H. and Brühl, J. and Sofiadis, K. and Zirkel, A. and Palikyras, S. and Mizi, A. and Li, Y. and Yigit, G. and Hoischen, A. and Frank, S. and Russ, N. and Trautwein, J. and van Bon, B. and Gilissen, C. and Laugsch, M. and Gusmao, E.G. and Josipovic, N. and Altmüller, J. and Nürnberg, P. and Längst, G. and Kaiser, F.J. and Watrin, E. and Brunner, H. and Rada-Iglesias, A. and Kurian, L. and Wollnik, B. and Bouazoune, K. and Papantonis, A.
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.
Keywords:Autophagy, Chromatin, Chromatin Assembly and Disassembly, DNA Damage, DNA Helicases, DNA-Binding Proteins, Epigenomics, Gene Editing, Gene Expression, Hallermann's Syndrome, Mutation, Nerve Tissue Proteins, Phenotype
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:3014
Date:21 May 2021
Official Publication:https://doi.org/10.1038/s41467-021-23327-1
PubMed:View item in PubMed

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