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PreprintCited by 4DNA Repair MechanismsUbiquitin and proteasome pathwaysTelomeres, Telomerase, and Senescence

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USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication

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Mackay, Hannah L., Stone, Helen R., Ellis, Katherine, Ronson, George E., Walker, Alexandra K., Starowicz, Katarzyna, Garvin, Alexander J., van Eijk, Patrick, Vaitsiankova, Alina, Vijayendran, Sobana, Beesley, James F., Petermann, Eva, Brown, Eric J., Densham, Ruth M., Reed, Simon H., Dobbs, Felix, Saponaro, Marco, Morris, Joanna R.·2024·Nature Communications
DOI 10.1101/2024.01.10.574674PMC PMC11405836

Preprint — published as 10.1038/s41467-024-52250-4 · Paper page

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Abstract

Mammalian DNA replication employs several RecQ DNA helicases to orchestrate the faithful duplication of genetic information. Helicase function is often coupled to the activity of specific nucleases, but how helicase and nuclease activities are co-directed is unclear. Here we identify the inactive ubiquitin-specific protease, USP50, as a ubiquitin-binding and chromatin-associated protein required for ongoing replication, fork restart, telomere maintenance and cellular survival during replicative stress. USP50 supports WRN:FEN1 at stalled replication forks, suppresses MUS81-dependent fork collapse and restricts double-strand DNA breaks at GC-rich sequences. Surprisingly we find that cells depleted for USP50 and recovering from a replication block exhibit increased DNA2 and RECQL4 foci and that the defects in ongoing replication, poor fork restart and increased fork collapse seen in these cells are mediated by DNA2, RECQL4 and RECQL5. These data define a novel ubiquitin-dependent pathway that promotes the balance of helicase: nuclease use at ongoing and stalled replication forks.

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Metadata

Authors
Mackay, H. L., Stone, H. R., Ellis, K., Ronson, G. E., Walker, A. K., Starowicz, K., Garvin, A. J., van Eijk, P., Vaitsiankova, A., Vijayendran, S., Beesley, J. F., Petermann, E., Brown, E. J., Densham, R. M., Reed, S. H., Dobbs, F., Saponaro, M., & Morris, J. R.
Affiliations
  • University of Birmingham (GB)
  • Cancer Research UK Clinical Trials Unit (GB)
  • University of Leeds (GB)
  • Cardiff University (GB)
  • University of Sussex (GB)
  • Queen Elizabeth Hospital Birmingham (GB)
  • University of Pennsylvania (US)
Corresponding author
Morris, Joanna R.
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2024-01-11
Volume
15
Issue
1
Pages
8102-8102
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2024.01.10.574674
PMC
PMC11405836
OpenAlex
W4402581122
Cited by
4
References
1
Citations by year
2026: 2 · 2025: 2
FWCI
0.54
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (publishedVersion, cc-by)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion, cc-by)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion, cc-by)
  • PubMed Central (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Wellcome Trust (206343/Z/17/Z)
  • Cancer Research UK (A19062, C8820/A28283, C8820/A19062, C8820)
  • University of Birmingham (C8820/A28283)
  • Medical Research Council (MR/X001008/1, MR/J007595/1)
  • Biotechnology and Biological Sciences Research Council (BB/S016155/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Keywords
ubiquitin-specific protease, RecQ helicase, RECQL4, RECQL5, DNA2 nuclease, FEN1, WRN, DNA replication, replication fork restart, stalled replication forks, telomere maintenance, replicative stress, hydroxyurea, pyridostatin, chromatin proteins

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