Ubiquitin-specific protease 21 stabilizes BRCA2 to control DNA repair and tumor growth

Jinping Liu, Alex Kruswick, Hien Dang, Andy D. Tran, So Mee Kwon, Xin Wei Wang and Philipp Oberdoerffer ()
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Jinping Liu: National Cancer Institute
Alex Kruswick: National Cancer Institute
Hien Dang: National Cancer Institute
Andy D. Tran: National Cancer Institute
So Mee Kwon: National Cancer Institute
Xin Wei Wang: National Cancer Institute
Philipp Oberdoerffer: National Cancer Institute

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Tumor growth relies on efficient DNA repair to mitigate the detrimental impact of DNA damage associated with excessive cell division. Modulating repair factor function, thus, provides a promising strategy to manipulate malignant growth. Here, we identify the ubiquitin-specific protease USP21 as a positive regulator of BRCA2, a key mediator of DNA repair by homologous recombination. USP21 interacts with, deubiquitinates and stabilizes BRCA2 to promote efficient RAD51 loading at DNA double-strand breaks. As a result, depletion of USP21 decreases homologous recombination efficiency, causes an increase in DNA damage load and impairs tumor cell survival. Importantly, BRCA2 overexpression partially restores the USP21-associated survival defect. Moreover, we show that USP21 is overexpressed in hepatocellular carcinoma, where it promotes BRCA2 stability and inversely correlates with patient survival. Together, our findings identify deubiquitination as a means to regulate BRCA2 function and point to USP21 as a potential therapeutic target in BRCA2-proficient tumors.

Date: 2017
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DOI: 10.1038/s41467-017-00206-2

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