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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., Rehimi, R., Kayserili, H., Brühl, J., Sofiadis, K., Zirkel, A., Palikyras, S., Mizi, A., Li, Y., Yigit, G., Hoischen, A., Frank, S., Russ, N., Trautwein, J., van Bon, B., Gilissen, C., Laugsch, M., Gusmao, E.G., Josipovic, N., Altmüller, J., Nürnberg, P., Längst, G., Kaiser, F.J., Watrin, E., Brunner, H., Rada-Iglesias, A., Kurian, L., Wollnik, B., 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 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 12 |
| Number: | 1 |
| 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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