Kargapolova, Yulia and Rehimi, Rizwan and Kayserili, Huelya and Bruehl, Joanna and Sofiadis, Konstantinos and Zirkel, Anne and Palikyras, Spiros and Mizi, Athanasia and Li, Yun and Yigit, Goekhan and Hoischen, Alexander and Frank, Stefan and Russ, Nicole and Trautwein, Jonathan and van Bon, Bregje and Gilissen, Christian and Laugsch, Magdalena and Gusmao, Eduardo Gade and Josipovic, Natasa and Altmueller, Janine and Nuernberg, Peter and Laengst, Gernot and Kaiser, Frank J. and Watrin, Erwan and Brunner, Han and Rada-Iglesias, Alvaro and Kurian, Leo and Wollnik, Bernd and Bouazoune, Karim and Papantonis, Argyris (2021) Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology. NATURE COMMUNICATIONS, 12 (1): 3014. ISSN 2041-1723,
Full text not available from this repository. (Request a copy)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: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-STRUCTURE; BINDING DOMAIN; CHROMATIN; MUTATIONS; GENE; STRESS; PBAF; TRANSLOCATION; PHENOTYPES; SMARCB1; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie > Lehrstuhl für Biochemie III > Prof. Dr. Gernot Längst |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 21 Sep 2022 09:15 |
| Last Modified: | 21 Sep 2022 09:15 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47820 |
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