ΔNp63-Senataxin circuit controls keratinocyte differentiation by promoting the transcriptional termination of epidermal genes.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35235452.
- Also identified by DOI 10.1073/pnas.2104718119 and PMC identifier 8915885.
- Licence recorded as CC BY-NC-ND.
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Abstract
SignificanceΔNp63 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.
Medical subject headings
- Cell Differentiation
- DNA Helicases
- Epidermis
- Keratinocytes
- Multifunctional Enzymes
- RNA Helicases
- Transcription Factors
- Transcription Termination, Genetic
- Tumor Suppressor Proteins