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

Autor: Kargapolova Y; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. ykargapo@uni-koeln.de.; Heart Center, University Hospital Cologne, Cologne, Germany. ykargapo@uni-koeln.de., Rehimi R; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Cluster of Excellence Cellular Stress Responses in Age-associated Disorders (CECAD), University of Cologne, Cologne, Germany., Kayserili H; Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey., Brühl J; Institute of Molecular Biology and Tumor Research, Philipps-University Marburg, Marburg, Germany., Sofiadis K; Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany., Zirkel A; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Palikyras S; Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany., Mizi A; Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany., Li Y; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany., Yigit G; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany., Hoischen A; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Frank S; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Institute of Neurophysiology, University of Cologne, Cologne, Germany.; Bayer AG, Wuppertal, Germany., Russ N; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Institute of Neurophysiology, University of Cologne, Cologne, Germany., Trautwein J; Institute of Molecular Biology and Tumor Research, Philipps-University Marburg, Marburg, Germany., van Bon B; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Gilissen C; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Laugsch M; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany., Gusmao EG; Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany., Josipovic N; Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany., Altmüller J; Cologne Center for Genomics, University of Cologne, Cologne, Germany., Nürnberg P; Cologne Center for Genomics, University of Cologne, Cologne, Germany., Längst G; Biochemistry Centre Regensburg (BRC), University of Regensburg, Regensburg, Germany., Kaiser FJ; Institute of Human Genetics, University Hospital Essen, Essen, Germany., Watrin E; Research Institute of Genetics and Development, Faculté de Médecine, Rennes, France., Brunner H; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Rada-Iglesias A; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Cluster of Excellence Cellular Stress Responses in Age-associated Disorders (CECAD), University of Cologne, Cologne, Germany.; Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), University of Cantabria, Santander, Spain., Kurian L; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Institute of Neurophysiology, University of Cologne, Cologne, Germany., Wollnik B; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.; Cluster of Excellence Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells (MBExC), University of Göttingen, Göttingen, Germany., Bouazoune K; Institute of Molecular Biology and Tumor Research, Philipps-University Marburg, Marburg, Germany. bouazoune@imt.uni-marburg.de., Papantonis A; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. argyris.papantonis@med.uni-goettingen.de.; Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany. argyris.papantonis@med.uni-goettingen.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 May 21; Vol. 12 (1), pp. 3014. Date of Electronic Publication: 2021 May 21.
DOI: 10.1038/s41467-021-23327-1
Abstrakt: 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.
Databáze: MEDLINE
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