The human HELQ helicase and XRN2 exoribonuclease cooperate in R-loop resolution

The human HELQ helicase is a superfamily 2, 3'-5 helicase homologous to POLQ and RNA helicases of the Ski2-like subfamily. It is involved in diverse aspects of DNA repair and is an emerging prognosis biomarker and novel drug target for cancer therapy. HELQ interacts with RPA through its inherently disordered N-HELQ domain and hence is recruited to RPA-bound DNA substrates. Our study reveals a novel role for HELQ in R-loop resolution. We show in cells and in vitro that HELQ is recruited by RPA at R-loops, which are then resolved if HELQ is catalytically active as an ATPase/helicase. Furthermore, we identify a functional interaction of HELQ with XRN2, a nuclear 5' to 3' exoribonuclease, which we suggest coordinates R-loop unwinding by HELQ with RNA digestion by XRN2. Collectively, we assign a new biological function for HELQ in genome stability in metazoans through its involvement with XRN2 in R-loop metabolism.