The most interesting paper I’ve read this year

We all know what the estrogen receptor is and what it does.  It’s a large protein with 3  functional components.  Actually there are several estrogen receptor proteins, but I’m going to discuss just one — Estrogen Receptor alpha (ERalpha).

Here are the components:

a DNA binding domain (which binds to stretches of bases called the Estrogen Response Element (ERE))

a domain which binds estrogen changing the conformation of the third domain which is —

a domain which binds to RNA polymerase II activating it so it transcribes genes into mRNA.

Given the complexity of the hormonal cycles, it is far from surprising that the estrogen receptor controls the levels of 15% of all annotated protein coding genes < Cell vol. 145 pp. 622 – 634 ’11 >.

Given its importance in breast cancer, ERalpha has been intensively studied for years.

Now various regions of proteins have been assigned function, the SH2 domain binds to phosphotyrosine in proteins, SH3 binds to proline rich motifs, RNA Binding Domains (RBDs) bind to (what else?) RNAs.  Each of them has a characteristic sequence of amino acids allowing them to be picked out from DNA sequences.

Enter Cell vol. 184 pp. 5086 – 5088, 5215 – 5229 ’21 where ERalpha was found to bind to over 1,200 messenger RNAs (mRNAs).   It was not supposed to do that as it doesn’t contain any RBDs (well at least the RBDs we knew about — back to the drawing board on that one).  Even more interesting is the fact what most of the mRNAs bound by ERalpha aren’t from the genes whose ERE ERalpha binds.

Life is said to have originated in the RNA world.  We all know about the big 3 important RNAs for the cell, mRNA, ribosomal RNA and transfer RNA.  But just like the water, sewer, power and subway systems under Manhattan, there is another world down there in the cell which doesn’t much get talked about.  These areRNAs, whose primary (and possibly only) function is to interact with other RNAs.

The RNA world is still alive and well in all our cells.  It’s like DOS still out there under Windows, or Unix and its command line under the Apple interface. We studied proteins and DNA because they were (relatively) easy to study.

The papers go on to study how ERalpha RNA binding affects cancer (which it does).

But there are far larger questions the work brings forth.

l. ERalpha is just one nuclear hormone receptor and Estrogen is just one hormone.  Do the nuclear hormone receptor for other hormones also bind RNA? Have we been missing some of their actions inside cells and if so there are mechanisms to exploit?

2. Why stop at nuclear hormone receptors?  ERalpha binds RNA with no RNA binding  domains (RBDs) in sight.  Do other proteins also bind RNAs and if so what does it mean?

Fantastic stuff.  There is a whole world of possibilities opening before our eyes thanks to these papers.

It reminds me of what an anatomy professor told us when we were studying neuroanatomy — ‘unfortunately everything is connected to everything else’.

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  • MStriker  On October 20, 2021 at 12:09 pm

    I’m getting the impression that we, despite being dominant in the macro world, are merely reflections/refractions of the micro world.

  • luysii  On October 20, 2021 at 8:32 pm

    I got the following back from one of the authors when I sent him the post — “This is the best press release/commentary for our paper! Well done, insightful and exciting! I love the link with the RNA world.”

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