Jmjd6 Catalyses Lysyl-Hydroxylation of U2AF65, a Protein Associated with RNA Splicing

Abstract

10. These authors contributed equally to the work.11. These authors contributed equally to the work. AbstractThe metazoan hypoxic response is regulated by the oxygen-dependent posttranslational hydroxylation of the -subunits of the hypoxia inducible factor (HIF)system. This identification has raised the question of whether other proteinhydroxylases are involved in the regulation of gene expression. Here we demonstrate that the splicing factor protein U2AF65 undergoes post-translational lysyl-5-hydroxylation as catalysed by the Fe(II) and 2-oxoglutarate dependent dioxygenaseJumonji domain-containing protein 6 (Jmjd6). Jmjd6 is a nuclear protein that has an important role in vertebrate development and is a close human homologue of the hypoxia inducible factor asparaginyl-hydroxylase. Jmjd6 is shown to regulate alternative RNA splicing of endogenous and reporter genes. The ability of Jmjd6 to influence the splicing pattern of all endogenous genes investigated supports a specific role for Jmjd6 in regulating RNA splicing. Main textMetazoan cells respond to limiting oxygen by activation of the hypoxia inducible factor (HIF) system(1). The HIF subunits are regulated by Fe(II) and 2-oxoglutarate

Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1

“…The hydroxylation reaction of Jmjd6 critically depends on the oxygen concentration; hence Jmjd6 is expected to be inhibited under conditions of severe hypoxia (19). Therefore, we investigated the effect of hypoxia on sFlt1 expression.…”

“…Jmjd6 was recently reported to hydroxylate the splicing factor U2AF65 (19). Therefore, we investigated whether U2AF65 might mediate Flt1 splicing and bind to Flt1 mRNA.…”

“…However, various following studies showed that Jmjd6 is localized in the nucleus (12)(13)(14)(15)(16) and is not involved in apoptotic cell clearance (17). Subsequently, a function as a histone arginine demethylase was identified (18) and a recent publication suggests that Jmjd6 regulates splicing by hydroxylating the splicing factor U2AF65 (19). Mice lacking Jmjd6 expression die perinatally and display cardiac developmental defects; however, it is unclear whether these mice have intrinsic defects of cells comprising the vasculature (17,20).…”

Selective inhibition of CD4 + T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors

“…Rahman et al have demonstrated that the conserved extraterminal domain of all three BET proteins, BRD2, BRD3, and BRD4, associates with several chromatin-modifying factors (29), which include the H3K36 methyltransferase NSD3 (30); ATAD5, a replication factor involved in the ATM/ATR-mediated DNA damage response (31,32); CHD4, a component of the transcriptional repressor mi-2/NURD complex that mediates nucleosome repositioning (33); and JMDJ6, originally reported to be a histone arginine demethylase but more recently implicated in lysyl hydroxylation of splicing factor U2AF65 (34,35). Further studies are needed to determine the roles of these chromatin modulators in T-cell differentiation.…”

From biological mechanisms to clinical implications: the role of mineral dust-induced gene in lung cancers

“…Oxygenase catalyzes hydroxylation of ribosomal proteins which regulate gene transcriptions (13). It is suggested that oxygenases also catalyze demethylation of N-ε-methyllysine histone residues (JmjC demethylases) (14) and lysyl 5-hydroxylation of splicing-related proteins (JMJD6) (15). Mdig/mina53 interacts with various ribosomal proteins and is involved in ribosome biogenesis (6) and ribosomal RNA transcription (12).…”