Gene of the Month – May: CHD6

Chromodomain-helicase-DNA-binding protein 6, encoded by the CHD6 gene, is a so-called chromatin remodeller. These proteins modify the chromatin architecture in the cell, thereby regulating the accessibility of genome regions to essential processes like the activation of transcription, DNA replication or DNA repair. CHD6 is a member of the CHD protein family, but its precise function has not yet been fully revealed. A recent study led by researchers from Göttingen now reports an important role played by CHD6 in the regulation of autophagy. Autophagy is one of several self-destruction mechanisms that cells use to react to stress or DNA damage.

The researchers started their exploration of CHD6 function by identifying a de novo missense mutation in CHD6 in a patient with the clinical phenotype of Hallermann-Streiff syndrome (HSS). HSS is a very rare congenital syndrome characterized, among other features, by multiple malformations and by premature ageing. Its genetic cause and underlying molecular mechanism have remained unknown so far. Extensive investigations performed in the study including assays on genome-edited cell models showed that CHD6 regulates the expression of autophagy-related genes. The identified mutation impaired the protein’s capability of recruiting certain co-factors in reaction to DNA damage or other stimuli. This resulted in dysregulated autophagy and accumulating DNA damage – both are known molecular hallmarks of ageing. The study published in Nature Communications provides the first explanation of a molecular mechanism underlying Hallermann-Streiff syndrome

Kargapolova Y, Rehimi R, Kayserili H, … Wollnik B, Bouazoune K, Papantonis A. Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology. Nat Commun. 2021 May 21;12(1):3014. doi: 10.1038/s41467-021-23327-1. [Epub ahead of print]

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