SmORFs and DWORFs — has molecular biology lost its mind?

There’s Plenty of Room at The Bottom is a famous talk given by Richard Feynman 56 years ago. He was talking about something not invented until decades later — nanotechnology. He didn’t know that the same advice now applies to molecular biology. The talk itself is well worth reading — here’s the link

Those not up to speed on molecular biology can find what they need at — Just follow the links (there are only 5) in the series.

lncRNA stands for long nonCoding RNA — nonCoding for protein that is. Long is taken to mean over 200 nucleotides. There is considerable debate concerning how many there are — but “most estimates place the number in the tens of thousands” [ Cell vol. 164 p. 69 ’16 ]. Whether they have any cellular function is also under debate. Could they be like the turnings from a lathe, produced by the various RNA polymerases we have (3 actually) simply transcribing the genome compulsively? I doubt this, because transcription takes energy and cells are a lot of things but wasteful isn’t one of them.

Where does Feynmann come in? Because at least one lncRNA codes for a very small protein using a Small Open Reading Frame (SMORF) to do so. The protein in question is called DWORF (for DWorf Open Reading Frame). It contains only 34 amino acids. Its function is definitely not trivial. It binds to something called SERCA, which is a large enzyme in the sarcoplasmic reticulum of muscle which allows muscle to relax after contracting. Muscle contraction occurs when calcium is released from the endoplasmic reticulum of muscle.  SERCA takes the released calcium back into the endoplasmic reticulum allowing muscle to contract. So repetitive muscle contraction depends on the flow and ebb of calcium tides in the cell. Amazingly there are 3 other small proteins which also bind to SERCA modifying its function. Their names are phospholamban (no kidding) sarcolipin and myoregulin — also small proteins of 52, 31 and 46 amino acids.

So here is a lncRNA making an oxymoron of its name by actually coding for a protein. So DWORF is small, but so are its 3 exons, one of which is only 4 amino acids long. Imagine the gigantic spliceosome which has a mass over 1,300,000 Daltons, 10,574 amino acids making up 37 proteins, along with several catalytic RNAs, being that precise and operating on something that small.

So there’s a whole other world down there which we’ve just begun to investigate. It’s probably a vestige of the RNA world from which life is thought to have sprung.

Then there are the small molecules of intermediary metabolism. Undoubtedly some of them are used for control as well as metabolism. I’ll discuss this later, but the Human Metabolome DataBase (HMDB) has 42,000 entries and METLIN, a metabolic database has 240,000 entries.

Then there is competitive endogenous RNA –

Do you need chemistry to understand this? Yes and no. How the molecules do what they do is the province of chemistry. The description of their function doesn’t require chemistry at all. As David Hilbert said about axiomatizing geometry, you don’t need points, straight lines and planes You could use tables, chairs and beer mugs. What is important are the relations between them. Ditto for the chemical entities making us up.

I wouldn’t like that.  It’s neat to picture in my mind our various molecular machines, nuts and bolts doing what they do.  It’s a much richer experience.  Not having the background is being chemical blind..  Not a good thing, but better than nothing.

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  • Bryan  On January 26, 2016 at 12:30 pm

    I think lncRNAs by definition are transcripts produced by Pol II (the other two polymerases, however, are involved in the production of many other types of noncoding RNAs).

    If cells are not wasteful, why do repetitive elements — essentially, the detritus leftover from retroviruses — make up ~50% of the human genome? Maybe the production of nonfunctional transcripts (i.e. the turnings from a lathe hypothesis) is not wasteful at all. For example, it might be the case that it takes more energy for the cell to completely silence all non-essential regions than it would to just allow for the occasional nonfunctional transcript to slip through the cracks.

    I would also not be surprised to see more lncRNAs be classified as coding for small proteins. Just as research in the past few decades has led to the discovery of the important role of small RNAs in biology, improved proteomics and genomic tools will probably lead to a better appreciation of the role of small peptides in biology. At the same time, I would also not be surprised to find various non-coding roles for coding RNAs as well.

  • luysii  On January 26, 2016 at 1:37 pm

    “I would also not be surprised to find various non-coding roles for coding RNAs as well.”

    That’s exactly what’s going on with the pseudogene for PTEN (which codes for an inactive enzyme) referred to in the link above. It has a premature termination codon, so it can’t be made into protein, but it acts like a sponge. Whether the mRNA for the pseudogene is a lncRNA or a coding RNA is a matter of semantics.

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