Nonproteolytic ubiquitination regulates chromatin occupancy by the NCoR/SMRT/HDAC3 corepressor complex in MCF-7 breast cancer cells

• DOI: 10.1073/pnas.2502805122
• Publication Date: 2025-04-30T23:29:01Z
• Authors: Giulio Ferrero; Maria Dafne Carda...; Francesca Luca; Eliot Bourk; Laura Ricci; Wen Liu; Yuan Gao; Giulia Burrone; Akhirah Muhammad; Stefanie Chan; Emma Smith; Ting-Yu Claire Fan; Santina Cutrupi; Ivan Garcia-Bassets; Michele De Bortoli; Michael G. Rosenfeld; Valentina Perissi
• Keywords: Corepressor; Chromatin immunoprecipitation

Tight regulation of gene expression is achieved through the coordinated action transcription factors and cofactors that often can act as both repressors activators in response to regulatory signals, with their activity modulated by context-specific signal transduction pathways also impinge on transient cyclical recruitment chromatin. However, mechanisms underlying intricate interplay between strategies controlling cofactors’ localization across subcellar domains remain poorly understood. Here, we investigated role G-Protein Pathway Suppressor 2 (GPS2), a transcriptional cofactor critical for maintaining cellular homeostasis via mitochondrial biogenesis, stress response, lipid metabolism, insulin signaling, inflammation, MCF-7 breast cancer cells. By integration biochemical assays genome-wide RNA sequencing Chromatin immunoprecipitation-Seq analyses, show nuclear GPS2 required licensing histone deacetylase 3 chromatin restricted ubiquitination tumor necrosis factor receptor-associated 6 (TRAF6), an E3 ubiquitin ligase previously shown regulate switch from repressive activating functions receptor corepressor (NCoR)/silencing mediator retinoic acid thyroid hormone (SMRT) complex here unexpectedly found translocate nucleus IL-1β stimulation. Nuclear TRAF6 recruited direct interaction corepressors NCoR/SMRT, TRAF6-mediated TGF-beta activated kinase 1 (MAP3K7) binding protein (TAB2), facultative component NCoR/SMRT complex, contributes clearance target regions. Together, these results reveal exquisite mechanism coordinating local proinflammatory signaling pathways.