SETX sumoylation: A link between DNA damage and RNA surveillance disrupted in AOA2.

Senataxin (SETX) is a putative RNA:DNA helicase that is mutated in two distinct juvenile neurological disorders, AOA2 and ALS4. SETX is involved in the response to oxidative stress and is suggested to resolve R loops formed at transcription termination sites or at sites of collisions between the transcription and replication machineries. R loops are hybrids between RNA and DNA that are believed to lead to DNA damage and genomic instability. We discovered that Rrp45, a core component of the exosome, is a SETX-interacting protein and that the interaction depends on modification of SETX by sumoylation. Importantly, we showed that AOA2 but not ALS4 mutations prevented both SETX sumoylation and the Rrp45 interaction. We also found that upon replication stress induction, SETX and Rrp45 co-localize in nuclear foci that constitute sites of R-loop formation generated by transcription and replication machinery collisions. We suggest that SETX links transcription, DNA damage and RNA surveillance, and discuss here how this link can be relevant to AOA2 disease.