In order to facilitate identification of new factors and mechanisms involved in this response, we have performed several distinct biological screens in parallel (proteomic and genomic screens). This was complemented by characterization of transcription and mRNA splicing after UV damage by various genome-wide techniques. Our 'multi-omic' approach explores the same process from various angles and places less emphasis on hits from an individual screen and instead focuses on factors that score in several screens. This has resulted in the identification of several new factors and unexplored mechanisms. We now investigate the function of several of these factors by the use of a multi-disciplinary approach, including biochemical and cell biological approaches as well as proteomics and genomics. Some of these studies have already been published. For example, we have shown that, at the level of gene expression, the UV damage response is associated with a shift from expression of long messenger RNAs (mRNAs) to shorter RNA transcript isoforms, due to alternative RNA splicing/termination (Williamson et al., Cell 2017; 168, p843-855). Notably, this includes a shift from a protein-coding ASCC3 mRNA to a shorter ASCC3 transcript isoform of which the 3’-noncoding region, rather than an encoded protein, is critical for transcription recovery after DNA damage. This study provides the first clear example of a gene that can encode both a protein (via its mRNA) and a regulatory, non-coding, RNA. Among several other important advances, we have also been studying transcriptional termination further, and the role of the SCAF4 and SCAF8 proteins in particular (Gregersen et al., Cell 2019; 177, 1797–1813). These proteins turn out to be the first examples of eukaryotic mRNA anti-terminator proteins. Likewise, a another recently published study on the connection between transcription stress and DNA damage showed that the well-known transcription elongation factor TFIIS is important to counteract transcription stress, R-loops and genome instability (Zatreanu et al., Molecular Cell 2019; 76, 57-69).
