ΔNp63-Senataxin circuit controls keratinocyte differentiation by promoting the transcriptional termination of epidermal genes.
Proc Natl Acad Sci U S A
; 119(10): e2104718119, 2022 03 08.
Article
in En
| MEDLINE
| ID: mdl-35235452
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transcription Factors
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Keratinocytes
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Cell Differentiation
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DNA Helicases
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RNA Helicases
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Tumor Suppressor Proteins
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Epidermis
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Transcription Termination, Genetic
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Multifunctional Enzymes
Limits:
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2022
Document type:
Article
Affiliation country:
Italy