UV irradiation remodels the specificity landscape of transcription factors.

Somatic mutations are highly enriched at transcription factor (TF) binding sites, with the strongest trend being observed for ultraviolet light (UV)-induced mutations in melanomas. One of the main mechanisms proposed for this hypermutation pattern is the inefficient repair of UV lesions within TF-binding sites, caused by competition between TFs bound to these lesions and the DNA repair proteins that must recognize the lesions to initiate repair. However, TF binding to UV-irradiated DNA is poorly characterized, and it is unclear whether TFs maintain specificity for their DNA sites after UV exposure. We developed UV-Bind, a high-throughput approach to investigate the impact of UV irradiation on protein-DNA binding specificity. We applied UV-Bind to ten TFs from eight structural families, and found that UV lesions significantly altered the DNA-binding preferences of all the TFs tested. The main effect was a decrease in binding specificity, but the precise effects and their magnitude differ across factors. Importantly, we found that despite the overall reduction in DNA-binding specificity in the presence of UV lesions, TFs can still compete with repair proteins for lesion recognition, in a manner consistent with their specificity for UV-irradiated DNA. In addition, for a subset of TFs, we identified a surprising but reproducible effect at certain nonconsensus DNA sequences, where UV irradiation leads to a high increase in the level of TF binding. These changes in DNA-binding specificity after UV irradiation, at both consensus and nonconsensus sites, have important implications for the regulatory and mutagenic roles of TFs in the cell.

Impact of year-long cannabis use for medical symptoms on brain activation during cognitive processes.

Importance: Cannabis is increasingly being used to treat medical symptoms, but the effects of cannabis use on brain function in those using cannabis for these symptoms is not known. Objective: To test whether brain activation during working memory, reward, and inhibitory control tasks, areas of cognition impacted by cannabis, showed increases following one year of cannabis use for medical symptoms. Design: This observational cohort study took place from July 2017 to July 2020 and is reported on in 2024. Setting: Participants were from the greater Boston area. Participants: Participants were recruited as part of a clinical trial based on seeking medical cannabis cards for anxiety, depression, pain, or sleep disorders, and were between 18 and 65 years. Exclusion criteria were daily cannabis use and cannabis use disorder at baseline. Main Outcomes and Measures: Outcomes were whole brain functional activation during tasks involving working memory, reward and inhibitory control at baseline and after one year of cannabis use. Results: Imaging was collected in participants before and one year after obtaining medical cannabis cards; 57 at baseline (38 female [66.7%]; mean [SD] age, 38.0 [14.6] years) at baseline, and 54 at one-year (37 female [68.5%]; mean [SD] age, 38.7 [14.3] years). Imaging was also collected in 32 healthy control participants (22 female [68.8%]; mean [SD] age, 33.8 [11.8] years) at baseline. In all groups and at both time points, functional imaging revealed canonical activations of the probed cognitive processes. No statistically significant difference in brain activation between the two timepoints (baseline and one-year) in those with medical cannabis cards and no association of changes in cannabis use frequency with brain activation were found. Conclusions and Relevance: Findings suggest that adults do not show significant neural effects in the areas of cognition of working memory, reward, and inhibitory control after one year of cannabis use for medical symptoms. The results warrant further studies that probe effects of cannabis at higher doses, with greater frequency, in younger age groups, and with larger, more diverse cohorts. Trial Registration: NCT03224468, https://clinicaltrials.gov/.