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

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

doi:10.1038/s41467-024-52250-4

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

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

^*Corresponding author for this work

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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.

Original language	English
Article number	8102
Number of pages	17
Journal	Nature Communications
Volume	15
DOIs	https://doi.org/10.1038/s41467-024-52250-4
Publication status	Published - 16 Sept 2024

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MackayH2024USP50Final published version, 3.36 MBLicence: Creative Commons: Attribution (CC BY)

1 Active
4 Finished

BRCA1 pathways in cancer predisposition and treatment.
Morris, J. (Principal Investigator), Beesley, J. (Co-Investigator), Starowicz, K. (Co-Investigator), Ronson, G. (Co-Investigator) & Mackay, H. (Co-Investigator)
Cancer Research Uk
1/01/20 → 31/12/25
Project: Research
Regulation of SUMO in DNA double-strand break repair.
Morris, J. (Principal Investigator)
The Wellcome Trust
11/12/17 → 11/01/23
Project: Research
Identifciation of the Second Tumour Suppressor Function of Brca1
Petermann, E. (Co-Investigator) & Morris, J. (Principal Investigator)
BREAST CANCER NOW
1/02/16 → 19/12/19
Project: Research
Ubiquitin processing in cancer development and treatment
Morris, J. (Principal Investigator) & Petermann, E. (Co-Investigator)
Cancer Research Uk
1/01/15 → 31/12/19
Project: Research
The BRCA1- Proteasome Link in Genotoxic Stress
Morris, J. (Principal Investigator)
BREAST CANCER CAMPAIGN
1/09/11 → 31/08/14
Project: Research

Cite this

Mackay, H. L., Stone, H. R., Ronson, G. E., Ellis, K., Lanz, A., Aghabi, Y., Walker, A. K., Starowicz, K., Garvin, A. J., Van Eijk, P., Koestler, S. A., Anthony, E. J., Piberger, A. L., Chauhan, A. S., Conway-Thomas, P., Vaitsiankova, A., Vijayendran, S., Beesley, J. F., Petermann, E., ... Morris, J. R. (2024). USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication. Nature Communications, 15, Article 8102. https://doi.org/10.1038/s41467-024-52250-4

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title = "USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication",

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.",

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

year = "2024",

month = sep,

day = "16",

doi = "10.1038/s41467-024-52250-4",

language = "English",

volume = "15",

journal = "Nature Communications",

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Mackay, HL , Stone, HR , Ronson, GE, Ellis, K, Lanz, A, Aghabi, Y, Walker, AK, Starowicz, K, Garvin, AJ, Van Eijk, P, Koestler, SA , Anthony, EJ , Piberger, AL , Chauhan, AS, Conway-Thomas, P, Vaitsiankova, A, Vijayendran, S, Beesley, JF, Petermann, E, Brown, EJ, Densham, RM, Reed, SH, Dobbs, F, Saponaro, M & Morris, JR 2024, 'USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication', Nature Communications, vol. 15, 8102. https://doi.org/10.1038/s41467-024-52250-4

TY - JOUR

T1 - USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication

AU - Mackay, Hannah L.

AU - Stone, Helen R.

AU - Ronson, George E.

AU - Ellis, Katherine

AU - Lanz, Alexander

AU - Aghabi, Yara

AU - Walker, Alexandra K.

AU - Starowicz, Katarzyna

AU - Garvin, Alexander J.

AU - Van Eijk, Patrick

AU - Koestler, Stefan A.

AU - Anthony, Elizabeth J.

AU - Piberger, Ann Liza

AU - Chauhan, Anoop S.

AU - Conway-Thomas, Poppy

AU - Vaitsiankova, Alina

AU - Vijayendran, Sobana

AU - Beesley, James F.

AU - Petermann, Eva

AU - Brown, Eric J.

AU - Densham, Ruth M.

AU - Reed, Simon H.

AU - Dobbs, Felix

AU - Saponaro, Marco

AU - Morris, Joanna R.

PY - 2024/9/16

Y1 - 2024/9/16

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-024-52250-4

DO - 10.1038/s41467-024-52250-4

M3 - Article

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

M1 - 8102

ER -

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

Abstract

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Projects

BRCA1 pathways in cancer predisposition and treatment.

Regulation of SUMO in DNA double-strand break repair.

Identifciation of the Second Tumour Suppressor Function of Brca1

Ubiquitin processing in cancer development and treatment

The BRCA1- Proteasome Link in Genotoxic Stress

Cite this