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.
Highlights
Tumor growth relies on efficient DNA repair to mitigate the detrimental impact of DNA damage associated with excessive cell division
We provide evidence that a defect in USP21-mediated BRCA2 stabilization impairs the growth of BRCA2-proficient hepatocellular carcinoma (HCC) tumor cells, and consistent with this, USP21 levels inversely correlate with HCC patient survival, pointing to USP21 as a potential target for HCC tumor therapy
We show that USP21 interacts with and deubiquitinates BRCA2 and that USP21 loss results in decreased BRCA2 expression in tumor cell lines
Summary
Tumor growth relies on efficient DNA repair to mitigate the detrimental impact of DNA damage associated with excessive cell division. HR is generally initiated by the PI3-like kinases ATM and ATR, which are activated by DSBs and stalled replication forks, respectively, to induce a cascade of posttranslational phosphorylation events, including the formation of S139-phosphorylated histone H2AX (γ-H2AX) at sites of DNA damage The latter facilitate the assembly of downstream HR effectors, most notably the breast and ovarian tumor suppressors BRCA1, BRCA2 and PALB2, which, together, promote DSB end resection and the formation of RAD51-coated single-stranded DNA (ssDNA) filaments required for homology search BRCA2 protein levels were further reported to correlate inversely with Skp[2] E3 ligase expression in prostate tumor tissue[25], and BRCA2 stabilization has been linked to sporadic breast cancer development[7] Both the mechanistic basis and physiological relevance of these observations remain to be investigated. USP21 presents a mediator of genome maintenance that may serve both as a therapeutic target and potential biomarker for HCC
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