Defining the function of the MiDEAS histone deacetylase complex at telomeric DNA
Embargo Date
2028-02-13
OA Version
Citation
Abstract
Telomeres cap chromosome ends and protect the integrity of the genome, shortening with each division- eventually causing cells to enter senescence. Cells that are primed to become cancerous can overcome replicative senescence and elongate their telomeres through either the reactivation of telomerase or via the alternative lengthening of telomeres (ALT) pathway. The prevalence of ALT across all cancers is approximately 10%; however, the prevalence of ALT in cancers of neuroepithelial and mesenchymal origin is estimated to be over 50%. These cancers have poor overall survival and limited treatment options, highlighting the ALT pathway as an opportunity for targeted therapeutic development. Early evidence demonstrated that telomeres in ALT positive cells displayed an increase in spontaneous DNA damage and telomere length heterogeneity, suggesting a reliance on recombination to promote telomere elongation. However, the exact mechanism that functions to regulate ALT activity has not been fully defined. Therefore, we used the proximity-labelling technology BioID to interrogate the ALT telomere proteome. One of the top hits of this screen was the mitotic deacetylase associated SANT domain protein MiDEAS. MiDEAS is part of the MiDAC complex, a class I histone deacetylase complex, suggesting that histone deacetylation may be critical for the regulation of ALT activity.
Description
2025