Pan J M, Betts H, Cubbon A, He L, Bolt E L, Soultanas P
Biodiscovery Institute, School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
Open Biol. 2025 Feb;15(2):240112. doi: 10.1098/rsob.240112. Epub 2025 Feb 19.
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 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.
人类HELQ解旋酶是一种2型超家族的3'-5解旋酶，与POLQ以及Ski2样亚家族的RNA解旋酶同源。它参与DNA修复的多个方面，是一种新兴的癌症治疗预后生物标志物和新型药物靶点。HELQ通过其固有无序的N-HELQ结构域与RPA相互作用，从而被招募到与RPA结合的DNA底物上。我们的研究揭示了HELQ在R环解决中的新作用。我们在细胞中表明，HELQ在R环处被RPA招募，如果HELQ作为ATP酶/解旋酶具有催化活性，R环随后会被解决。此外，我们确定了HELQ与XRN2（一种核5'至3'外切核糖核酸酶）之间的功能相互作用，我们认为这种相互作用协调了HELQ对R环的解旋与XRN2对RNA的消化。总体而言，我们通过HELQ与XRN2参与R环代谢，为其在多细胞生物基因组稳定性中赋予了新的生物学功能。
