USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication
Mammalian DNA replication relies on various DNA helicase and nuclease activities to ensure accurate genetic duplication, but how different helicase and nuclease activities are properly directed remains unclear. Here, we identify the ubiquitin-specific protease, USP50, as a chromatin-associated protein required to promote ongoing replication, fork restart, telomere maintenance, cellular survival following hydroxyurea or pyridostatin treatment, and suppression of DNA breaks near GC-rich sequences. We find that USP50 supports proper WRN-FEN1 localisation at or near stalled replication forks. Nascent DNA in cells lacking USP50 shows increased association of the DNA2 nuclease and RECQL4 and RECQL5 helicases and replication defects in cells lacking USP50, or FEN1 are driven by these proteins. Consequently, suppression of DNA2 or RECQL4/5 improves USP50-depleted cell resistance to agents inducing replicative stress and restores telomere stability. These data define an unexpected regulatory protein that promotes the balance of helicase and nuclease use at ongoing and stalled replication forks.
Authors
- Felix Dobbs
- Stefan A. Koestler (ORCID: https://orcid.org/0000-0002-7223-8291)
- Patrick van Eijk (ORCID: https://orcid.org/0000-0001-9549-555X)
- Yara Aghabi (ORCID: https://orcid.org/0000-0003-1517-4428)
- Helen R Stone
- Ruth M. Densham (ORCID: https://orcid.org/0000-0003-4490-2842)
- James Beesley
- Alexandra K. Walker
- Alexander J. Lanz
- Eva Petermann (ORCID: https://orcid.org/0000-0002-5746-213X)
- Marco Saponaro (ORCID: https://orcid.org/0000-0002-9302-2553)
- Anoop Singh Chauhan (ORCID: https://orcid.org/0000-0001-8722-2404)
- Katherine Ellis (ORCID: https://orcid.org/0000-0003-4382-7967)
- Alina Vaitsiankova (ORCID: https://orcid.org/0000-0002-9355-0903)
- Katarzyna Starowicz (ORCID: https://orcid.org/0000-0002-9144-8630)
- George E. Ronson (ORCID: https://orcid.org/0000-0002-2424-8401)
- Ann Liza Piberger
- Hannah L. Mackay
- Joanna R. Morris (ORCID: https://orcid.org/0000-0001-9762-8133)
- Alexander J. Garvin (ORCID: https://orcid.org/0000-0002-2669-3170)
- Simon H. Reed (ORCID: https://orcid.org/0000-0002-4711-0560)
- Eric J. Brown (ORCID: https://orcid.org/0000-0001-6562-6512)
- Sobana Vijayendran
- Elizabeth J. Anthony (ORCID: https://orcid.org/0000-0002-5927-7472)
- Poppy Conway-Thomas
Institutions
- European Bioinformatics Institute (GB)
- University of Leeds (GB)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- University of Sussex (GB)
- Queen Elizabeth Hospital Birmingham (GB)
- Columbia University Irving Medical Center (US)
- Cancer Research UK Clinical Trials Unit (GB)
- NIHR Birmingham Biomedical Research Centre (GB)
- Cardiff University (GB)
- University of Pennsylvania (US)
- University of Birmingham (GB)
- University of Sheffield (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1038/s41467-024-52250-4
- Citations
- 2
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.47
Funders
- Cancer Research UK
- University of Birmingham
- Medical Research Council
- Biotechnology and Biological Sciences Research Council