AsianScientist (May 27, 2015) – MYC—a well known oncogenic protein that is found abundantly cancer cells—has been shown to direct influences a set of components which control alternative splicing. The findings, published in Nature, show how MYC safeguards proper pre-messenger-RNA splicing as an essential step in lymphomagenesis.
In most human cancers, elevated levels of MYC is linked to a poor prognosis. On the other hand, MYC is also required in many normal functions of a cell; therefore, regulation of MYC expression is crucial for cell survival. However, the molecules which directly interact with MYC under cancer conditions are still largely unknown.
In the present study, a team of researchers led by Drs. Cheryl Koh and Marco Bezzi from the Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), have found that MYC directly induced the transcription of genes encoding core splicing machinery components in both human and mouse lymphoma models.
Among the targets up-regulated was the gene encoding the critical enzymatic subunit protein arginine methyltransferase 5 (PRMT5). High levels of PRMT5 accurately predicted bad prognosis/survival in patients with large diffuse B-cell lymphomas. Therefore, the group experimented by removing PRMT5 in mice with lymphoma and discovered that tumor development was delayed, implicating PRMT5 in MYC-driven tumorigenesis.
However, the complete removal of PRMT5 is detrimental, as was shown in a previous paper by the same lab, resulting in severe developmental defects and consequently, death.
Using bioinformatics, they then conducted next generation sequencing (RNA-sequencing) of transgenic mice with B-cell lymphoma that had PRMT5 removed, to discover genes that were improperly spliced as a result of this coupled reaction. Via computational analysis of the affected sites discovered in the genome, they were able to design specific antisense oligonucleotides (ASOs) to replicate the effects of PRMT5 deletion. ASOs are currently being used in clinics as a viable therapeutic molecule.
The results point to a potential use of targeted antisense oligonucleotides to regulate the levels of PRMT5 activity or other members of the splicing machinery. However, tight controls would have to be put in place to monitor its regulation to prevent the potentially detrimental side effects.
The article can be found at: Koh et al. (2015) MYC Regulates the Core Pre-mRNA Splicing Machinery as an Essential Step in Lymphomagenesis.
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Copyright: Asian Scientist Magazine; Photo: Institute of Molecular and Cell Biology.
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