Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detailed molecular analysis using whole-exome, whole-genome, and RNA sequencing of 27 RDEB SCC tumors, including multiple tumors from the same patient and multiple regions from five individual tumors. We report that driver mutations were shared with spontaneous, ultraviolet (UV) light-induced cutaneous SCC (UV SCC) and head and neck SCC (HNSCC) and did not explain the early presentation or aggressive nature of RDEB SCC. Instead, endogenous mutation processes associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) deaminases dominated RDEB SCC. APOBEC mutation signatures were enhanced throughout RDEB SCC tumor evolution, relative to spontaneous UV SCC and HNSCC mutation profiles. Sixty-seven percent of RDEB SCC driver mutations was found to emerge as a result of APOBEC and other endogenous mutational processes previously associated with age, potentially explaining a >1000-fold increased incidence and the early onset of these SCCs. Human papillomavirus-negative basal and mesenchymal subtypes of HNSCC harbored enhanced APOBEC mutational signatures and transcriptomes similar to those of RDEB SCC, suggesting that APOBEC deaminases drive other subtypes of SCC. Collectively, these data establish specific mutagenic mechanisms associated with chronic tissue damage. Our findings reveal a cause for cancers arising at sites of persistent inflammation and identify potential therapeutic avenues to treat RDEB SCC.

Linked Comment: Uitto. Br J Dermatol 2020; 182:526–527. Plain language summary available online

Allopolyploidization, the combination of the genomes from two different species, has been a major source of evolutionary innovation and a driver of speciation and environmental adaptation. In plants, it has also contributed greatly to crop domestication, as the superior properties of many modern crop plants were conferred by ancient allopolyploidization events. It is generally thought that allopolyploidization occurred through hybridization events between species, accompanied or followed by genome duplication. Although many allopolyploids arose from closely related species (congeners), there are also allopolyploid species that were formed from more distantly related progenitor species belonging to different genera or even different tribes. Here we have examined the possibility that allopolyploidization can also occur by asexual mechanisms. We show that upon grafting--a mechanism of plant-plant interaction that is widespread in nature--entire nuclear genomes can be transferred between plant cells. We provide direct evidence for this process resulting in speciation by creating a new allopolyploid plant species from a herbaceous species and a woody species in the nightshade family. The new species is fertile and produces fertile progeny. Our data highlight natural grafting as a potential asexual mechanism of speciation and also provide a method for the generation of novel allopolyploid crop species.

Mitochondrial complex II (succinate dehydrogenase) is part of the tricarboxylic acid cycle and the respiratory chain. Three nuclear genes encode its essential iron-sulfur subunit in Arabidopsis (Arabidopsis thaliana). One of them, SUCCINATE DEHYDROGENASE2-3 (SDH2-3), is specifically expressed in the embryo during seed maturation, suggesting that SDH2-3 may have a role as the complex II iron-sulfur subunit during embryo maturation and/or germination. Here, we present data demonstrating that three abscisic acid-responsive elements and one RY-like enhancer element, present in the SDH2-3 promoter, are involved in embryo-specific SDH2-3 transcriptional regulation. Furthermore, we show that ABSCISIC ACID INSENSI-TIVE3 (ABI3), FUSCA3 (FUS3), and LEAFY COTYLEDON2, three key B3 domain transcription factors involved in gene expression during seed maturation, control SDH2-3 expression. Whereas ABI3 and FUS3 interact with the RY element in the SDH2-3 promoter, the abscisic acid-responsive elements are shown to be a target for bZIP53, a member of the basic leucine zipper (bZIP) family of transcription factors. We show that group S1 bZIP53 protein binds the promoter as a heterodimer with group C bZIP10 or bZIP25. To the best of our knowledge, the SDH2-3 promoter is the first embryo-specific promoter characterized for a mitochondrial respiratory complex protein. Characterization of succinate dehydrogenase activity in embryos from two homozygous sdh2-3 mutant lines permits us to conclude that SDH2-3 is the major iron-sulfur subunit of mature embryo complex II. Finally, the absence of SDH2-3 in mutant seeds slows down their germination, pointing to a role of SDH2-3-containing complex II at an early step of germination.

Mutations in the gene encoding collagen VII cause the devastating blistering disease recessive dystrophic epidermolysis bullosa (RDEB). RDEB is characterized by severe skin fragility and nonhealing wounds aggravated by scarring and fibrosis. We previously showed that TSP1 is increased in RDEB fibroblasts. Because transforming growth factor-b (TGF-b) signaling is also increased in RDEB, and TSP1 is known to activate TGF-b, we investigated the role of TSP1 in TGF-b signaling in RDEB patient cells. Knockdown of TSP1 reduced phosphorylation of smad3 (a downstream target of TGF-b signaling) in RDEB primary fibroblasts, whereas overexpression of collagen VII reduced phosphorylation of smad3. Furthermore, inhibition of TSP1 binding to the LAP/TGF-b complex decreased fibrosis in engineered extracellular matrix formed by RDEB fibroblasts, as evaluated by picrosirius red staining and analyses of birefringent collagen fibrillar deposits. We show that collagen VII binds TSP1, which could potentially limit TSP1-LAP association and subsequent TGF-b activation. Our study suggests a previously unreported mechanism for increased TGF-b signaling in the absence of collagen VII in RDEB patient skin. Moreover, these data identify TSP1 as a possible target for reducing fibrosis in the tumor-promoting dermal microenvironment of RDEB patients.

Five muscle fibre types (I, IIc, IIa, IIx and IIb) were found in the suprahyoid muscles (mylohyoid, geniohyoid, and the anterior and posterior bellies of the digastric) of the rat using immuno and enzyme histochemical techniques. More than 90 % of fibres in the muscles examined were fast contracting fibres (types IIa, IIx and IIb). The geniohyoid and the anterior belly of the digastric had the greatest number of IIb fibres, whilst the mylohyoid was almost exclusively formed by aerobic fibres. The posterior belly of the digastric contained a greater percentage of aerobic fibres (83n4 %) than the anterior belly (67n8 %). With the exception of the geniohyoid, the percentage of type I and IIc fibres, which have slow myosin heavy chain (MHCβ), was relatively high and greater than has been previously reported in the jaw-closing muscles of the rat, such as the superficial masseter. The geniohyoid and mylohyoid exhibited a mosaic fibre type distribution, without any apparent regionalisation, although in the later MHCβ-containing fibres (types I and IIc) were primarily located in the rostral 2\3 region. In contrast, the anterior and posterior bellies of the digastric revealed a clear regionalisation. In the anterior belly of the digastric 2 regions were observed : both a central region, which was almost exclusively formed by aerobic fibres and where all of the type I and IIc fibres were located, and a peripheral region, where type IIb fibres predominated. The posterior belly of the digastric showed a deep aerobic region which was greater in size and where type I and IIc fibres were confined, and a superficial region, where primarily type IIx and IIb fibres were observed.

Highlights d HMGB1 controls transition from pre-cancerous to cancerous lesions in skin d Epithelial HMGB1 promotes neutrophil recruitment and NET formation d TNF and RIPK1 activity mediate HMGB1-dependent NET formation and skin tumorigenesis d NET formation occurs in lesional and tumor-associated skin of RDEB patients

Recessive dystrophic epidermolysis bullosa is a painful condition characterised by repeated blistering of the skin. Von Bischhoffshausen et al. report that in this condition, small sensory fibres in the skin are injured leading to neuropathic pain. These findings support the use of neuropathic pain treatment in recessive dystrophic epidermolysis bullosa.