Author
Listed:
- Roopesh Anand
(The Francis Crick Institute)
- Erika Buechelmaier
(Memorial Sloan Kettering Cancer Center
Graduate School of Medical Sciences, Weill Cornell Medicine)
- Ondrej Belan
(The Francis Crick Institute)
- Matthew Newton
(The Francis Crick Institute)
- Aleksandra Vancevska
(The Francis Crick Institute)
- Artur Kaczmarczyk
(Faculty of Medicine, Imperial College London
MRC-London Institute of Medical Sciences)
- Tohru Takaki
(The Francis Crick Institute)
- David S. Rueda
(Faculty of Medicine, Imperial College London
MRC-London Institute of Medical Sciences)
- Simon N. Powell
(Memorial Sloan Kettering Cancer Center)
- Simon J. Boulton
(The Francis Crick Institute)
Abstract
DNA double-stranded breaks (DSBs) are deleterious lesions, and their incorrect repair can drive cancer development1. HELQ is a superfamily 2 helicase with 3′ to 5′ polarity, and its disruption in mice confers germ cells loss, infertility and increased predisposition to ovarian and pituitary tumours2–4. At the cellular level, defects in HELQ result in hypersensitivity to cisplatin and mitomycin C, and persistence of RAD51 foci after DNA damage3,5. Notably, HELQ binds to RPA and the RAD51-paralogue BCDX2 complex, but the relevance of these interactions and how HELQ functions in DSB repair remains unclear3,5,6. Here we show that HELQ helicase activity and a previously unappreciated DNA strand annealing function are differentially regulated by RPA and RAD51. Using biochemistry analyses and single-molecule imaging, we establish that RAD51 forms a complex with and strongly stimulates HELQ as it translocates during DNA unwinding. By contrast, RPA inhibits DNA unwinding by HELQ but strongly stimulates DNA strand annealing. Mechanistically, we show that HELQ possesses an intrinsic ability to capture RPA-bound DNA strands and then displace RPA to facilitate annealing of complementary sequences. Finally, we show that HELQ deficiency in cells compromises single-strand annealing and microhomology-mediated end-joining pathways and leads to bias towards long-tract gene conversion tracts during homologous recombination. Thus, our results implicate HELQ in multiple arms of DSB repair through co-factor-dependent modulation of intrinsic translocase and DNA strand annealing activities.
Suggested Citation
Roopesh Anand & Erika Buechelmaier & Ondrej Belan & Matthew Newton & Aleksandra Vancevska & Artur Kaczmarczyk & Tohru Takaki & David S. Rueda & Simon N. Powell & Simon J. Boulton, 2022.
"HELQ is a dual-function DSB repair enzyme modulated by RPA and RAD51,"
Nature, Nature, vol. 601(7892), pages 268-273, January.
Handle:
RePEc:nat:nature:v:601:y:2022:i:7892:d:10.1038_s41586-021-04261-0
DOI: 10.1038/s41586-021-04261-0
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