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

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Chromodomain-helicase-DNA binding (CHD) proteins are crucial chromatin remodelers involved in various human diseases.
• CHD6 is a less-understood member of the CHD protein family, with its role in pathology largely unexplored.

Purpose of the Study:

• To investigate the role of CHD6 in the rare Hallermann-Streiff syndrome (HSS).
• To elucidate the molecular mechanisms by which a CHD6 mutation leads to HSS pathogenesis.

Main Methods:

• Genome editing was employed to create isogenic induced pluripotent stem cell (iPSC) lines modeling HSS.
• Genomic, in vivo, and in vitro assays were utilized to analyze CHD6 function.
• The study examined CHD6's interaction with autophagy and stress response genes.

Main Results:

• A de novo CHD6 missense mutation was identified in an HSS patient.
• The identified HSS mutation impairs CHD6 protein folding and its recruitment of co-remodelers.
• Cells with the mutation showed impaired DNA damage repair and autophagy, leading to increased DNA damage and senescence.

Conclusions:

• The study uncovers a molecular mechanism linking HSS to impaired chromatin remodeling by CHD6.
• Disruption of autophagic flux and genotoxic stress surveillance by mutated CHD6 contributes to HSS development.
• This research highlights CHD6's critical role in maintaining genomic stability and cellular homeostasis.