Journal Article

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

Piberger, Ann Liza, Reed, Simon H., Beesley, James F., Mackay, Hannah L., Dobbs, Felix, Van Eijk, Patrick, Ellis, Katherine, Garvin, Alexander J., Ronson, George E., Chauhan, Anoop S., Aghabi, Yara, Morris, Joanna R., Anthony, Elizabeth J., Saponaro, Marco, Brown, Eric J., Conway-Thomas, Poppy, Koestler, Stefan A., Starowicz, Katarzyna, Lanz, Alexander, Walker, Alexandra K., Densham, Ruth M., Vijayendran, Sobana, Stone, Helen R., Petermann, Eva, Vaitsiankova, Alina

2024

Overview

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. Mammalian DNA replication relies on various helicases and nucleases to ensure accurate genetic duplication, but how these enzymes are properly directed is unclear. Here, the authors identify USP50 as a key protein for promoting ongoing replication, restarting stalled forks, maintaining telomeres, and ensuring cell survival.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/51 / 14/63 / 38/15 / 38/70 / 49 / 631/337/151 / 631/337/151/1431 / 631/337/151/2356 / Cell survival / Chromatin / Chromatin - metabolism / Deoxyribonucleic acid / DNA / DNA biosynthesis / DNA damage / DNA helicase / DNA Helicases - genetics / DNA Helicases - metabolism / DNA Replication - drug effects / FEN1 protein / Flap Endonucleases - genetics / Flap Endonucleases - metabolism / Gene sequencing / HEK293 Cells / HeLa Cells / Humanities and Social Sciences / Humans / Hydroxyurea / Mammals / multidisciplinary / Nuclease / Nucleotide sequence / Proteins / RecQ Helicases - genetics / RecQ Helicases - metabolism / RecQ protein / Replication / Replication forks / Science / Science (multidisciplinary) / Survival / Telomere - genetics / Telomere - metabolism / Telomere Homeostasis - drug effects / Telomeres / Ubiquitin-Specific Proteases - genetics / Ubiquitin-Specific Proteases - metabolism / Ubiquitin-specific proteinase / Werner Syndrome Helicase - genetics / Werner Syndrome Helicase - metabolism