Tag Archives: trimethylation oflysine

Junk that isn’t

The more we understand, the more we realize how little we’ve understood what we thought we understood.   Here is a double example.

We have 1,400,000 Alu elements in our genome.  They are about 300 nucleotides long, meaning that there is over 1 every 3,000 nucleotides in our 3,200,000,000 nucleotide genome.  They don’t code for protein, and were widely thought to be junk, selfish genes whose only role was to ensure that the organism carrying them, kept them along as they reproduced.

This post contains a heavy dose of contemporary molecular biology.  If you’re a little shaky on some of it have a look at — https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/ — and follow the links.

Not so says Proc. Natl. Acad. Sci. vol. 117 pp. 415 – 425  ’20.  They are part of several important physiologic processes (1) T lymphocyte activation (2) heat shock stress (3) endoplasmic reticulum stress.  All 3 cause transcription of Alu’s by RNA polymerase III (pol III).

All RNA levels increase with heat shock, including RNAs made from Alu elements.  They bind directly and tightly (nanoMolar affinity) to RNA polymerase II (which transcribes protein coding genes) and co-occupy the promoters of repressed genes, preventing transcription of these genes and protein synthesis of them.  At least that was the state of play 11 years ago (PNAS 105 5569 – 5574 ’09)

This paper notes that Alu is not passive, but actually a self-cleaving ribozyme (an enzyme made of RNA), an entirely new role.  When complexed with another protein EZH2 (a polycomb protein thought to be a transcriptional repressor using its lysine methylation activity), the rate of Alu self-cleavage increases by 40%.

So what?

In addition to stoping transcription, Alu also retards transcription elongation.  So stress increases in EZH2 causes Alu to cleave itself faster, turning off  repression and improving the responses to the 3 types of stresses above.

So we really didn’t understand both Alu which has been studied for years, or EZH2 a polycomb protein (ditto).  Alu is a self-cleaving ribozyme, and EZH2 doesn’t just turn off genes by its enzymatic activity (lysine trimethylation), but binds to an RNA so it can cleave itself faster (e.g. its a cofactor).

Fascinating and humbling to see how much there is to know about things we thought we knew.  But it’s also exciting.  Who knows what else is out there to discover about the known, never mind the known unknowns.