Melanocytes are dendritic, pigment-producing cells located in the skin and are responsible for its protection against the deleterious effects of solar ultraviolet radiation (UVR), which include DNA damage and elevated reactive oxygen species (ROS). They do so by synthesizing photoprotective melanin pigments and distributing them to adjacent skin cells (e.g., keratinocytes). However, melanocytes encounter a large burden of oxidative stress during this process, due to both exogenous and endogenous sources. Therefore, melanocytes employ numerous antioxidant defenses to protect themselves; these are largely regulated by the master stress response transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2). Key effector transcriptional targets of NRF2 include the components of the glutathione and thioredoxin antioxidant systems. Despite these defenses, melanocyte DNA often is subject to mutations that result in the dysregulation of the proliferative mitogen-activated protein kinase (MAPK) pathway and the cell cycle. Following tumor initiation, endogenous antioxidant systems are co-opted, a consequence of elevated oxidative stress caused by metabolic reprogramming, to establish an altered redox homeostasis. This altered redox homeostasis contributes to tumor progression and metastasis, while also complicating the application of exogenous antioxidant treatments. Further understanding of melanocyte redox homeostasis, in the presence or absence of disease, would contribute to the development of novel therapies to aid in the prevention and treatment of melanomas and other skin diseases

Craniosynostosis, the premature ossification of cranial sutures, is a developmental disorder of the skull vault, occurring in approximately 1 in 2250 births. The causes are heterogeneous, with a monogenic basis identified in ~25% of patients. Using whole-genome sequencing, we identified a novel, de novo variant in BCL11B, c.7C>A, encoding an R3S substitution (p.R3S), in a male patient with coronal suture synostosis. BCL11B is a transcription factor that interacts directly with the nucleosome remodelling and deacetylation complex (NuRD) and polycomb-related complex 2 (PRC2) through the invariant proteins RBBP4 and RBBP7. The p.R3S substitution occurs within a conserved amino-terminal motif (RRKQxxP) of BCL11B and reduces interaction with both transcriptional complexes. Equilibrium binding studies and molecular dynamics simulations show that the p.R3S substitution disrupts ionic coordination between BCL11B and the RBBP4–MTA1 complex, a subassembly of the NuRD complex, and increases the conformational flexibility of Arg-4, Lys-5 and Gln-6 of BCL11B. These alterations collectively reduce the affinity of BCL11B p.R3S for the RBBP4–MTA1 complex by nearly an order of magnitude. We generated a mouse model of the BCL11B p.R3S substitution using a CRISPR-Cas9-based approach, and we report herein that these mice exhibit craniosynostosis of the coronal suture, as well as other cranial sutures. This finding provides strong evidence that the BCL11B p.R3S substitution is causally associated with craniosynostosis and confirms an important role for BCL11B in the maintenance of cranial suture patency.

Ultraviolet B (UVB) radiation is a primary cause of DNA damage in the skin, which is often a precursor to skin cancer. Natural products represent a rich source of compounds with unexplored photoprotective properties. Our previous work identified 3-methoxybenzyl isothiocyanate (MBITC), a meadowfoam derivative, as a promising UVB-absorptive agent that reduces DNA damage and cell proliferation; however, its clinical use is limited by dose-dependent cytotoxicity. To address this, we synthesized a novel amide lipid conjugate of MBITC, N-(3-methoxybenzyl)eicos-5-enamide (MBA), and evaluated its photoprotective efficacy and mechanism of action. Our findings demonstrate that MBA exhibited remarkably reduced cytotoxicity compared to its parent compound, while effectively retaining its photoprotective properties. In human primary keratinocyte cultures, MBA significantly reduced UVB-induced DNA damage, as evidenced by a decrease in cyclobutane pyrimidine dimers (p < 0.05) and γ-H2A.X (p < 0.05). Furthermore, MBA increased the expression of DNA damage response (DDR) proteins and DNA damage-binding protein 1 (DDB1) (p < 0.05) and the activation of Ataxia Telangiectasia and Rad3-related protein (ATR) (p < 0.05), a master regulator of DDR and repair pathways. These findings suggest that MBA acts through direct UVB absorption and/or the engagement of DDR pathways following irradiation, highlighting its potential use as a novel photoprotective compound.