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

Yulia Kargapolova (), Rizwan Rehimi, Hülya Kayserili, Joanna Brühl, Konstantinos Sofiadis, Anne Zirkel, Spiros Palikyras, Athanasia Mizi, Yun Li, Gökhan Yigit, Alexander Hoischen, Stefan Frank, Nicole Russ, Jonathan Trautwein, Bregje Bon, Christian Gilissen, Magdalena Laugsch, Eduardo Gade Gusmao, Natasa Josipovic, Janine Altmüller, Peter Nürnberg, Gernot Längst, Frank J. Kaiser, Erwan Watrin, Han Brunner, Alvaro Rada-Iglesias, Leo Kurian, Bernd Wollnik, Karim Bouazoune () and Argyris Papantonis ()
Additional contact information
Yulia Kargapolova: University of Cologne
Rizwan Rehimi: University of Cologne
Hülya Kayserili: Koç University School of Medicine
Joanna Brühl: Philipps-University Marburg
Konstantinos Sofiadis: University Medical Center Göttingen
Anne Zirkel: University of Cologne
Spiros Palikyras: University Medical Center Göttingen
Athanasia Mizi: University Medical Center Göttingen
Yun Li: University Medical Center Göttingen
Gökhan Yigit: University Medical Center Göttingen
Alexander Hoischen: Radboud University Medical Center
Stefan Frank: University of Cologne
Nicole Russ: University of Cologne
Jonathan Trautwein: Philipps-University Marburg
Bregje Bon: Radboud University Medical Center
Christian Gilissen: Radboud University Medical Center
Magdalena Laugsch: University of Cologne
Eduardo Gade Gusmao: University Medical Center Göttingen
Natasa Josipovic: University Medical Center Göttingen
Janine Altmüller: University of Cologne
Peter Nürnberg: University of Cologne
Gernot Längst: University of Regensburg
Frank J. Kaiser: University Hospital Essen
Erwan Watrin: Faculté de Médecine
Han Brunner: Radboud University Medical Center
Alvaro Rada-Iglesias: University of Cologne
Leo Kurian: University of Cologne
Bernd Wollnik: University Medical Center Göttingen
Karim Bouazoune: Philipps-University Marburg
Argyris Papantonis: University of Cologne

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-23327-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23327-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-23327-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().