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

Mackay, Hannah L., Stone, Helen R., Ronson, George E., Ellis, Katherine, Lanz, Alexander, Aghabi, Yara, Walker, Alexandra K., Starowicz, Katarzyna, Garvin, Alexander J., Van Eijk, Patrick ORCID: https://orcid.org/0000-0001-9549-555X, Koestler, Stefan A., Anthony, Elizabeth J., Piberger, Ann Liza, Chauhan, Anoop S., Conway-Thomas, Poppy, Vaitsiankova, Alina, Vijayendran, Sobana, Beesley, James F., Petermann, Eva, Brown, Eric J., Densham, Ruth M., Reed, Simon H. ORCID: https://orcid.org/0000-0002-4711-0560, Dobbs, Felix, Saponaro, Marco and Morris, Joanna R. 2024. USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication. Nature Communications 15 , 8102. 10.1038/s41467-024-52250-4

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Abstract

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	17 September 2024
Date of Acceptance:	30 August 2024
Last Modified:	17 Sep 2024 09:00
URI:	https://orca.cardiff.ac.uk/id/eprint/172159

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