Transcription of mRNA-encoding genes underpins all life. Most fundamental processes in cells and organisms are regulated at the level of transcription.
DNA damage in genes can directly give rise to harmful mutations, but it can also obstruct the progress of transcribing RNA polymerase II (RNAPII), thereby blocking gene expression. A repair pathway has evolved that specifically targets lesions that stop RNAPII during its journey across a gene, so-called transcription-coupled nucleotide excision repair (TC-NER). Damage-stalled RNAPII can also be removed by ubiquitylation/degradation, clearing the gene for repair by other means.
While transcription is essential and therefore protected by a variety of mechanisms, it also comes at a cost for genome integrity. For example, high levels of transcription are correlated with breaks at fragile chromosome sites, mutagenesis and elevated levels of DNA recombination.
Research into how the genome-destabilising effects of transcription are minimized is still at a very early stage, but insights into this research area is essential for our understanding of the regulatory mechanisms at play in the interface between transcription and other DNA-related processes, as well as for the understanding of processes underlying genome instability.
Our laboratory studies the mechanisms of transcription, with particular emphasis on transcript elongation in human cells, using a wide range of experimental approaches, ranging from reconstitution biochemistry using purified proteins, over proteomics and genomics, to cell biological and genomic screening techniques.