Open AccessΔNp63-Senataxin circuit controls keratinocyte differentiation by promoting the transcriptional termination of epidermal genes
Author(s) -
Veronica Gatti,
Cláudia Fernanda,
Mirco Compag,
Veronica La Banca,
Alessandro Mauriello,
Manuela Montanaro,
Stefano Scalera,
Francesca De Nicola,
Eleonora Candi,
Francesco Ricci,
Luca Fania,
Gerry Melino,
Angelo Peschiaroli
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2104718119
Subject(s) - keratinocyte , biology , keratin , microbiology and biotechnology , cellular differentiation , gene expression , gene , transcriptional regulation , regulation of gene expression , regulator , transcription factor , genetics , cell culture
Significance ΔNp63 is a master regulator of skin homeostasis since it finely controls keratinocyte differentiation and proliferation. Here, we provide cellular and molecular evidence demonstrating the functional role of a ΔNp63 interactor, the R-loop–resolving enzyme Senataxin (SETX), in fine-tuning keratinocyte differentiation. We found that SETX physically binds the p63 DNA–binding motif present in two early epidermal differentiation genes, Keratin 1 (KRT1) and ZNF750, facilitating R-loop removal over their 3′ ends and thus allowing efficient transcriptional termination and gene expression. These molecular events translate into the inability of SETX-depleted keratinocytes to undergo the correct epidermal differentiation program. Remarkably, SETX is dysregulated in cutaneous squamous cell carcinoma, suggesting its potential involvement in the pathogenesis of skin disorders.