RLOOP-AS · Interconnection between R-loops and co-transcriptional alternative splicing

Interconnection between R-loops and co-transcriptional alternative splicing

Gene expression is an extremely complex mechanism involving several cellular machineries and sub-mechanisms. One of these mechanisms, called alternative splicing, is able to produce different proteins from one unique gene and understanding its regulation is of utmost importance, as mutations in its components are responsible for diseases and cancers. Notably, it has been demonstrated that UV light deregulates alternative splicing of genes important for cell survival and this might be responsible for skin cancer progression. However, the mechanistic insights remain unknown and deciphering them will help for the development of new therapeutic approaches. It has also been shown that mutations in several splicing factors are able to stabilize R-loop formation, which happens when the nascent RNA invade the DNA duplex before the formation of the double helix. The single stranded DNA strand might then be attacked by damaging agents creating genome instability. However, if persistent R-loop formation could be a threat for the genome integrity, the controlled formation of R-loop was recently shown to regulate gene expression. The aim of this project was to study the possible connection between R-loop formation and alternative splicing regulation, especially after DNA damage induction, and to understand the underlying mechanisms of regulation. We focused on RNA polymerase II kinetics and epigenetic modifications, as previous studies linked these two mechanisms with alternative splicing regulation. We have shown that after DNA damage, notably induced by UV light, R-loops were quickly formed, before alternative splicing was affected and that removal of R-loops could prevent alternative splicing alterations, suggesting a regulatory role of R-loops after DNA damage.

Data: CORDIS, © European Union