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

作者：Liu Jinping; Kruswick Alex; Dang Hien; Tran Andy D; Kwon So Mee; Wang Xin Wei; Oberdoerffer Philipp

来源：Nature Communications, 2017, 8(1): 137.

DOI：10.1038/s41467-017-00206-2

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

• 出版日期2017-7-26