The role of Jade-1 in DNA mismatch damage and repair in renal cancer
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The von Hippel-Lindau (VHL) tumor suppressor pVHL is lost in 90% of clear-cell renal-cell carcinomas (ccRCCs). Jade-1 is a renal tumor suppressor that is normally stabilized by pVHL. MutS Homolog2 (MSH2) is a key initiator in DNA mismatch repair (MMR). Defects in MMR are associated with genome-wide instability and predisposition to certain types of cancer. Mass spectrometry data of immunoprecipitated Flag-tagged Jade-1 lysates showed signal for MSH2, suggesting Jade-1 may participate in MMR. Here, we confirmed an interaction between endogenous MSH2 and endogenous Jade-1 by coimmunoprecipitation. Using cell fractionation, we found that MSH2 and Jade-1 translocated to the nucleus in response to alkylating agent MNNG in kidney proximal tubule cells. We also visualized the translocation of Jade-1 by immunofluorescence. Silencing JADE1 also influenced the kinetics of MSH2 translocation. In addition, by colony forming assay, JADE1-silenced cells were resistant to mismatch damage induced by MNNG, which is a feature of cells with an MMR defect. Furthermore, reintroducing pVHL into renal cancer cells also changed the amount of translocated MSH2 and Jade-1. In contrast to wild-type mice, Jade1 heterozygous mice got spontaneous tumors, and those tumors continued to show heterozygosity for Jade1. Taken together, our results identify a mechanism for Jade-1 regulation of MMR through its nuclear translocation. pVHL may also contribute to MSH2 and Jade-1 translocation by increasing Jade-1 abundance. These findings establish an early role for Jade-1 in MMR, provide further indication that Jade-1 helps maintain genomic stability in the kidney and support that Jade-1 is a haploinsufficient renal tumor suppressor.