Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology.
Nat Commun
; 12(1): 3014, 2021 05 21.
Article
em En
| MEDLINE
| ID: mdl-34021162
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Autofagia
/
Dano ao DNA
/
DNA Helicases
/
Proteínas do Tecido Nervoso
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article