BMB Section Seminar: "Ribosome hydroxylase Mina53 is required for Glioblastoma and is involved in regulation of translation rate and fidelity by regulating ribosomal biogenesis"
Deo Prakash Pandey, Postdoc in Kristian Helins group, Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Denmark
MINA53–Mn–2OG–RPL27A(32–50). Modified from doi:10.1038/nature13263.
Glioblastoma multiforme (GBM) is one of the most aggressive types of tumors with a poor response to standard treatment and a median 5-year survival of less than 5%. Therefore, there is an urgent need for new treatments. Recently, a large number of genome-wide studies have shown that the epigenetic modifiers are frequently deregulated in cancer. Using a mouse GBM model, we performed in vitro and in vivo shRNA screens to identify epigenetic regulators required for the tumorigenic process in GBM. Among these regulators is a ribosome hydroxylase Mina53 which hydroxylates His-39 of ribosomal protein, RPL27a. We have found that the knock-down (KD) of Mina53 reduces the in vitro proliferation and colony forming ability of mouse glioma initiating cells (mGIC) and this is dependent on the catalytic activity of Mina. Furthermore, Mina KD in mGICs resulted into their reduced ability to form tumors and thus marked an increased survival of injected mice with mGICs. We found that Mina KD strongly reduced the in vitro proliferation and colony forming ability of cells derived from the glioma patients. Knock-down of Mina resulted into a small but significant reduction in the global protein synthesis rate. A tandem affinity purification experiment to identify proteins associated with Mina revealed that it is associated mainly with ribosomal proteins, including its substrate RPL27a. Global proteomic analyses revealed that final amounts and de novo protein synthesis of many ribosomal proteins were reduced upon Mina depletion. Isolation and identification of different polysome fraction bound mRNAs using high-throughput sequencing found that mRNAs encoding many ribosomal proteins have lower number of ribosomes loaded on them in the Mina depleted samples compared to the control. Taken together, this study has found that Mina53 is required for glioblastoma and it regulates translation through regulation of ribosomal biogenesis.