ΔNp63-Senataxin circuit controls keratinocyte differentiation by promoting the transcriptional termination of epidermal genes

Gatti, Veronica; Fernanda, Cláudia; Compagnone, Mirco; Banca, Veronica La; Mauriello, Alessandro; Montanaro, Manuela; Scalera, Stefano; Nicola, Francesca De; Candi, Eleonora; Ricci, Francesco; Fania, Luca; Melino, Gerry; Peschiaroli, Angelo

doi:10.1073/pnas.2104718119

Cited by 22 publications

(22 citation statements)

References 47 publications

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“…This has led many authors to propose that SETX directly resolves R-loops by unwinding the RNA:DNA hybrid portion of R-loops, therefore promoting the restoration of the natural double-stranded DNA. However, transcription, which is the major source of R-loops, is also substantially altered by SETX depletion (60–62, 72). A couple of recent studies have shown that the perturbations of RNAPII genomic distribution provoked by SETX deletion/depletion are rather associated with R-loop losses at many loci (81, 82).…”

Section: Discussionmentioning

confidence: 99%

“…However, it remains possible that SETX rather controls R-loop formation by acting on RNAPII genomic occupancy. Indeed, SETX has been implicated in RNAPII transcription termination (38,(60)(61)(62) although it is unclear whether SETX has retained the ability of its yeast orthologue to induce termination or whether it rather plays an accessory role in this process.…”

Section: Introductionmentioning

confidence: 99%

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Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor

Hašanová

Klapstova

Porrúa

et al. 2022

Preprint

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Prolonged pausing of the transcription machinery may lead to the formation of three-stranded nucleic acid structures, called R-loops, typically resulting from the annealing of the nascent RNA with the template DNA. Unscheduled persistence of R-loops and RNA polymerases may interfere with transcription itself and other essential processes such as DNA replication and repair. Senataxin (SETX) is a putative helicase, mutated in two neurodegenerative disorders, which has been implicated in the control of R-loop accumulation and in transcription termination. However, understanding the precise role of SETX in these processes has been precluded by the absence of a direct characterisation of SETX biochemical activities. Here, we purify and characterise the helicase domain of SETX in parallel with its yeast orthologue, Sen1. Importantly, we show that SETX is a bona fide helicase with the ability to resolve R-loops. Furthermore, SETX has retained the transcription termination activity of Sen1 but functions in a species-specific manner. Finally, subsequent characterisation of two SETX variants harbouring disease-associated mutations shed light into the effect of such mutations on SETX folding and biochemical properties. Altogether, these results broaden our understanding of SETX function in gene expression and the maintenance of genome integrity and provide clues to elucidate the molecular basis of SETX-associated neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor

Hašanová

Klapstova

Porrúa

et al. 2022

Preprint

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“…CKs are a heterogeneous group of proteins that contribute to the structure of intermediate filament that function as the supporting cytoskeleton in the epithelial cells [ 15 ]. The type I CKs consist of acidic proteins, arranged in pairs of heterotypic keratin chains, and the type II are basic or neutral proteins which are arranged in pairs of heterotypic keratin chains co-expressed during differentiation of simple and stratified epithelial tissues [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

Antigenicity Preservation Is Related to Tissue Characteristics and the Post-Mortem Interval: Immunohistochemical Study and Literature Review

et al. 2022

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The main aim of this study was to investigate the post-mortem proteolytic degradation process of selected tissue antigens and correlate it to the post-mortem interval. During the autopsy of 12 cadavers (time interval ranging 1 day–2 years after death) samples of skin, liver, kidney, and spleen were collected. All samples were formalin-fixed and paraffin-embedded. Four µm paraffin sections were used for hematoxylin–eosin staining and immunohistochemical analysis (Ki67, Vimentin, Pan cytokeratin, and CD20). Data reported here show that immunohistochemical reactivity preservation was related to the characteristics of the tissues. In particular, the most resistant tissue was the skin, where the autolysis phenomena were not appreciable before 5 days. On the contrary, the liver and the spleen underwent early autolysis, while the kidney displayed an early autolysis of the tubules and a late one of the glomeruli. As concerns specific antigens, immunoreactivity was lost earliest for nuclear antigens as compared to cytoplasmic ones. In conclusion, our results demonstrate that immunohistochemical detection of specific antigens may be useful in estimating the post-mortem interval, especially when we need to know whether the post-mortem interval is a few days or more than 7–10 days.

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“…Both ΔNp63 and SETX physically bind the p63 DNA-binding motif present in early epidermal differentiation genes, in order to facilitate R-loop removal and allow efficient transcriptional termination. Interestingly, SETX expression is deregulated in cutaneous SCC, indicating that ΔNp63 and SETX interaction is important in skin pathologies [ 96 ]. To sustain proliferation and wound repair in keratinocytes, ΔNp63 interacts with nuclear factor erythroid 2-related factor 2 (NFE2L2; NRF2).…”

Section: Exploiting the P63 Interactome In Epithelial Development And...mentioning

confidence: 99%

Distinct interactors define the p63 transcriptional signature in epithelial development or cancer

Pecorari

Bernassola

Melino

et al. 2022

Biochemical Journal

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The TP63 is an indispensable transcription factor for development and homeostasis of epithelia and its derived glandular tissue. It is also involved in female germline cell quality control, muscle and thymus development. It is expressed as multiple isoforms transcribed by two independent promoters, in addition to alternative splicing occurring at the mRNA 3′-UTR. Expression of the TP63 gene, specifically the amino-deleted p63 isoform, ΔNp63, is required to regulate numerous biological activities, including lineage specification, self-renewal capacity of epithelial stem cells, proliferation/expansion of basal keratinocytes, differentiation of stratified epithelia. In cancer, ΔNp63 is implicated in squamous cancers pathogenesis of different origin including skin, head and neck and lung and in sustaining self-renewal of cancer stem cells. How this transcription factor can control such a diverse set of biological pathways is central to the understanding of the molecular mechanisms through which p63 acquires oncogenic activity, profoundly changing its down-stream transcriptional signature. Here, we highlight how different proteins interacting with p63 allow it to regulate the transcription of several central genes. The interacting proteins include transcription factors/regulators, epigenetic modifiers, and post-transcriptional modifiers. Moreover, as p63 depends on its interactome, we discuss the hypothesis to target the protein interactors to directly affect p63 oncogenic activities and p63-related diseases.

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ΔNp63-Senataxin circuit controls keratinocyte differentiation by promoting the transcriptional termination of epidermal genes

Cited by 22 publications

References 47 publications

Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor

Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor

Antigenicity Preservation Is Related to Tissue Characteristics and the Post-Mortem Interval: Immunohistochemical Study and Literature Review

Distinct interactors define the p63 transcriptional signature in epithelial development or cancer

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