MYCN and NCYM – A curious case of positive feedback loop and brand new gene evolution

I’ve never told you anything about my bachelor’s thesis. Well guess what? It was about MYCN and NCYM. During my bachelor internship I had the chance to work in a Neuroblastoma research group, and thus, I focussed on this infantile neuronal cancer for my thesis.

MYCN is an important gene in NB research: it is a trascription factor that regulates about 15% of all human genes. Between these genes there are plenty for cellular biomass and cell metabolism regulation that are mostly deregulated in cancers. MYCN is overamplified in 18-20% of NB cases and this causes an overexpression of its protein product. MYCN overexpression has been associated with bad prognosis, high aggressiveness and metastasis.

MYCN is known, being a transcription factor, to promote also its own transcription. But in normal condition MYCN is phosphorilated by GSK3Β and degraded in the cell. But a new player has entered the battle: NCYM!

NCYM is a MYCN antisense gene, which means that it is transcribed in the opposite sense of MYCN even though they share most of the sequence. So MYCN and NCYM are antisense genes and guess what? MYCN also promotes NCYM expression!

What it’s really interesting from the regulation point of view is that NCYM helps MYCN back. It turns out that NCYM interacts with mTOR-S6K kinases pathway, helping the phosphorilation of GSK3Β that of course decreases MYCN phosphorilation and thus, decreasing its degradation.

We have therefore established a positive feedback loop between MYCN and NCYM: MYCN promotes its own transcription and NCYM transcription, while NCYM promotes MYCN stabilization through phosphorilation pathways. Examples like these make me really think about gene and cell regulation and how amazing it is! Such level of precision and control brought to life by evolution!

Where A is MYCN and B is NCYM 😉

There is another interesting bit from this example! Apparently NCYM evolved de novo by itself. Think about it: normally a gene evolves either from transposition or duplication from previously existing genes. But NCYM, being an antisense gene shared part of the sequence with MYCN (in the other sense) even before its existence. Technically we can have a gene born from scratch, we just need a initially non-coding sequence to turn into coding. This is what must have happened to the NCYM gene! All of a sudden a promoter favored this gene expression in an antisense way of MYCN and its product managed to find a role in the loop with time!

NCYM is both an amazing example of feedback loop and of evolutionary curiosity. Apparently is the first de novo evolved gene in humans of which the function has been clearly identified!

It’s impressive how you can find the hands of evolution in the most curious places. As a molecular biologist these kind of thing make me jump of excitment! Not enough for you? Let me tell you another story..


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