Abstract
Author SummaryJMJD6 belongs to the Jumonji C domain-containing family of proteins. The majority of this family are histone demethylases implicated in chromatin-associated events, but there have also been some reports of lysyl hydroxylase activity for JMJD6. Here we report a new posttranslational modification for the tumor suppressor protein p53 that is mediated by JMJD6. Via a physical associations with p53, JMJD6 catalyzes the hydroxylation of p53, thereby repressing its transcriptional activity. Depletion of JMJD6 promotes cell apoptosis, arrests cells in the G1 phase, sensitizes cells to DNA damaging agent-induced cell death, and represses p53-dependent colon cell proliferation and tumorigenesis. Significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.
Highlights
Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins
The results indicated that JMJD6 was co-purified with several proteins including cleavage and polyadenylation specific factor 6 (CPSF6), heterogeneous nuclear ribonucleoprotein A2/B1, putative RNA-binding protein Luc7-like 2, and JMJD6 itself, which was reported to form homo-oligomer (Figure 1A and Table S1) [46,47]
Five matching peptides from the tumor suppressor protein p53 were identified in the JMJD6containing protein complex (Figure 1A), suggesting that JMJD6 is associated with p53 in vivo
Summary
Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. JMJD6 has been described as either a histone demethylase to remove the methyl moieties on histone H3 at arginine 2 (H3R2) and histone H4 at arginine 3 (H4R3) [4] or as a lysyl hydroxylase to target U2AF65 [5], a protein associated with RNA splicing. These observations clearly indicate that the biological function of JMJD6 might be multidimensional. Given current understanding of Jumonji C domain-containing proteins in controlling a wide range of biological functions, the importance and multitude of the cellular activity of JMJD6 is expected
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