The HelQ human DNA repair helicase utilizes a PWI-like domain for DNA loading through interaction with RPA, triggering DNA unwinding by the HelQ helicase core

Jenkins, Tabitha; Northall, Sarah J; Ptchelkine, Denis; Lever, Rebecca; Cubbon, Andrew; Betts, Hannah; Taresco, Vincenzo; Cooper, Christopher D O; McHugh, Peter J; Soultanas, Panos; Bolt, Edward L

Abstract

Genome instability is a characteristic enabling factor for carcinogenesis. HelQ helicase is a component of human DNA maintenance systems that prevent or reverse genome instability arising during DNA replication. Here, we provide details of the molecular mechanisms that underpin HelQ function — its recruitment onto ssDNA through interaction with RPA, and subsequent translocation of HelQ along ssDNA. We describe for the first time a functional role for the non-catalytic N-terminal region of HelQ, by identifying and characterising its PWI-like domain. We present evidence that this domain of HelQ mediates interaction with RPA that orchestrates loading of the helicase domains onto ssDNA. Once HelQ is loaded onto the ssDNA, ATP-Mg2+ binding in the catalytic site activates the helicase core and triggers translocation along ssDNA as a dimer. Furthermore, we identify HelQ-ssDNA interactions that are critical for the translocation mechanism. Our data are novel and detailed insights into the mechanisms of HelQ function relevant for understanding how human cells avoid genome instability provoking cancers, and also how cells can gain resistance to treatments that rely on DNA crosslinking agents.

Citation

Jenkins, T., Northall, S. J., Ptchelkine, D., Lever, R., Cubbon, A., Betts, H., Taresco, V., Cooper, C. D. O., McHugh, P. J., Soultanas, P., & Bolt, E. L. (2021). The HelQ human DNA repair helicase utilizes a PWI-like domain for DNA loading through interaction with RPA, triggering DNA unwinding by the HelQ helicase core. NAR Cancer, 3(1), Article zcaa043. https://doi.org/10.1093/narcan/zcaa043

• Journal Article Type: Article
• Acceptance Date: Dec 8, 2020
• Online Publication Date: Jan 12, 2021
• Publication Date: 2021-03
• Deposit Date: Jan 9, 2021
• Publicly Available Date: Jan 18, 2021
• Journal: NAR Cancer
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 1
• Article Number: zcaa043
• DOI: https://doi.org/10.1093/narcan/zcaa043
• Public URL: https://nottingham-repository.worktribe.com/output/5154038
• Publisher URL: https://academic.oup.com/narcancer/article/3/1/zcaa043/6089195