Arginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair

Pilar Sanchez-Bailon; Soo Choi; Elizabeth Dufficy; Karan Sharma; Gavin McNee; Emma  Gunnell; Kelly Chiang; Debashish Sahay; Sarah Maslen; Grant Stewart; Mark Skehel; Ingrid  Dreveny; Clare Davies

doi:10.1038/s41467-021-26413-6

Arginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair

Pilar Sanchez-Bailon, Soo Choi, Elizabeth Dufficy, Karan Sharma, Gavin McNee, Emma Gunnell, Kelly Chiang, Debashish Sahay, Sarah Maslen, Grant Stewart, Mark Skehel, Ingrid Dreveny, Clare Davies

Cancer and Genomic Sciences

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Abstract

Cross-talk between distinct protein post-translational modifications is critical for an effective DNA damage response. Arginine methylation plays an important role in maintaining genome stability, but how this modification integrates with other enzymatic activities is largely unknown. Here, we identify the deubiquitylating enzyme USP11 as a previously uncharacterised PRMT1 substrate, and demonstrate that the methylation of USP11 promotes DNA end-resection and the repair of DNA double strand breaks (DSB) by homologous recombination (HR), an event that is independent from another USP11-HR activity, the deubiquitylation of PALB2. We also show that PRMT1 is a ubiquitylated protein that it is targeted for deubiquitylation by USP11, which regulates the ability of PRMT1 to bind to and methylate MRE11. Taken together, our findings reveal a specific role for USP11 during the early stages of DSB repair, which is mediated through its ability to regulate the activity of the PRMT1-MRE11 pathway.

Original language	English
Article number	6313
Number of pages	18
Journal	Nature Communications
Volume	12
Issue number	1
Early online date	2 Nov 2021
DOIs	https://doi.org/10.1038/s41467-021-26413-6
Publication status	Published - Dec 2021

Bibliographical note

Funding Information:
We thank members of the Birmingham Centre for Genome Biology (BCGB) for helpful discussion (particularly Jo Morris, Ruth Densham, and Steve Smerdon for PRMT1 modelling), Gaetano Gargiulo (MDC, Berlin), and Stephane Richard (McGill University, Canada) for his kind gift of the methyl-deficient MRE11 plasmids. This work was supported by funds exclusively awarded to C.C.D. by an MRC NIRG (MR/M009912/1) and a CRUK programme grant (C52376/A25500). E.G. was supported by the Medical Research Council [1501569], G.S.M. and G.S.S. are supported by a CRUK programme grant (C17183/A23303).

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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1 Finished
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Investigating the role of PRMT5 in cancer
Kanhere, A. & Davies, C.
Cancer Research Uk
1/05/18 → 30/04/25
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The role of PRMT1-Mediated arginine methylation during breast cancer development
Davies, C.
Medical Research Council
21/05/15 → 20/11/18
Project: Research Councils

Cite this

Sanchez-Bailon, P., Choi, S., Dufficy, E., Sharma, K., McNee, G., Gunnell, E., Chiang, K., Sahay, D., Maslen, S., Stewart, G., Skehel, M., Dreveny, I., & Davies, C. (2021). Arginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair. Nature Communications, 12(1), Article 6313 . https://doi.org/10.1038/s41467-021-26413-6

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abstract = "Cross-talk between distinct protein post-translational modifications is critical for an effective DNA damage response. Arginine methylation plays an important role in maintaining genome stability, but how this modification integrates with other enzymatic activities is largely unknown. Here, we identify the deubiquitylating enzyme USP11 as a previously uncharacterised PRMT1 substrate, and demonstrate that the methylation of USP11 promotes DNA end-resection and the repair of DNA double strand breaks (DSB) by homologous recombination (HR), an event that is independent from another USP11-HR activity, the deubiquitylation of PALB2. We also show that PRMT1 is a ubiquitylated protein that it is targeted for deubiquitylation by USP11, which regulates the ability of PRMT1 to bind to and methylate MRE11. Taken together, our findings reveal a specific role for USP11 during the early stages of DSB repair, which is mediated through its ability to regulate the activity of the PRMT1-MRE11 pathway.",

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AU - Gunnell, Emma

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Arginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair

Abstract

Bibliographical note

ASJC Scopus subject areas

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Projects

Investigating the role of PRMT5 in cancer

The role of PRMT1-Mediated arginine methylation during breast cancer development

Cite this