New insight into the relationship between UV damage formation, transcription and mutagenesis. Elisheva Heilbrun, and Sheera Adar Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel Canada, Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem, 91120, Israel. DNA damages induced by ultraviolet (UV) radiation in sunlight block RNA and DNA polymerases and can lead to cell death, mutations, and skin cancer. Recent cancer mutagenesis studies have found that UV-induced mutational patterns are asymmetric along transcribed genes, with lower mutagenesis on transcribed strand attributed to transcription-coupled repair. The major damages induced by ultraviolet (UV) radiation in sunlight are cyclobutane pyrimidine dimers (CPDs). High resolution mapping of these damages in human cells revealed the major determinant of UV-damage formation is the primary sequence of the genome. Studying the patterns of these damages at transcribed regions we uncovered a transcriptional asymmetry in DNA damage formation, that is explained by the asymmetric distribution of damage-forming di-nucleotides in the primary sequence of the DNA. This asymmetry is conserved in vertebrates and invertebrates and is completely reversed between introns and exons. We show the transcriptional asymmetry in introns is linked to the transcription process itself, and is also found in enhancer elements. In contrast, the asymmetry in exons is not correlated to expression, and is associated with codon usage preferences. Our results highlight the importance of considering the primary sequence of the DNA in determining DNA damage sensitivity and mutagenic potential.