The role of the exosome in gene transcription and DNA repair

Eukaryotic genomes produce a large variety of non-coding RNAs (ncRNAs).

Some ncRNAs are transcribed from bona-fide genes, but others are produced by “pervasive” transcription of exposed genomic regions.

Recent research carried out by us and others has demonstrated that pervasive ncRNAs are transcribed from DNA double-strand breaks (DSBs) in response to DNA damage, and that DSB repair relies on a delicate balance between ncRNA production and degradation.

An important player in the degradation of damage-induced ncRNAs is the exosome, a multiprotein complex that degrades many RNAs in the cell nucleus. The exosome contains an inactive core and two subunits with ribonuclease activity: EXOSC10 and DIS3. We have previously shown that EXOSC10 is required for degradation of damage-induced ncRNAs and for DSBs repair.

We will combine molecular biology, biochemistry and microscopy methods to continue studying how damage-induced transcription and ncRNA degradation contribute to DNA repair in human cells.

Our aims are 1) understand how gene context and transcription influence the choice of DSB repair pathway, 2) explore mechanisms by which the exosome contributes to maintain the stability of the genome, and 3) elucidate the function of DIS3 in DNA repair.

The discovery of RNA involved in DNA repair has unveiled an unforeseen dimension of the DNA damage response, and understanding the synthesis, function and degradation of the damage-induced ncRNAs is a highly relevant research goal.