I remember being introduced to RNA as a disposable DNA copy with a very short life, a sort of mayfly of the molecular world.
RNA was how you got from DNA to protein. It was like a set of instructions printed on the most brittle of papers. It might as well have been the medium through which the Mission: Impossible team got their assignment before it self-destructed. In one word, it was uninteresting.
We’re all familiar with DNA. It encodes the machinery that creates living beings. But RNA, its oft-dismissed offspring, is much more fascinating.
To understand why I called RNA a “disposable copy”, we must be familiar with the central dogma of molecular biology, which is quite simple. DNA makes RNA. RNA makes proteins.
First off, a detour into architecture.
DNA is like an architectural drawing constructed on a computer. This drawing contains all the instructions to build a mansion, and includes all sorts of comments, early drafts, and meta-data that will not be needed by the construction crew. So a paper copy of that is printed out and purged of the non-essential elements.
This paper copy is the RNA. It can be torn, and stained, and burnt. It has a certain fragility. And it must be transported from the central hub of the architectural firm to the construction zone.
The builders will then use this paper copy to put together building blocks in the right order and create an actual structure. This structure, which has a purpose, is the protein.
So why should we care about the paper copy? Because RNA is much more than that. It helps explain why we have so few genes, how they are regulated, and how we get diseases. And it could also lead to truly exciting technologies.
You may remember one of the biggest surprises out of the Human Genome Project and subsequent research: expecting 50,000 to 100,000 genes, scientists discovered humans only had about 19,000. But the number of distinct RNA molecules used for protein production was much higher than this, so how could this be explained?
When genes are transcribed into RNA (or when we select the part of the drawing we want to print out), segments of the gene are left out. You can imagine a gene as a long necklace string onto which you slide a few beads, spaced out. When the RNA is made, only the equivalent of the beads is conserved, not the bit of string in between the beads. This is a process known as “splicing”. Now imagine that the beads are numbered sequentially. What if we were to keep beads 1, 2, and 3 for one RNA molecule, and beads 1, 3, and 4 for another? We’d have two different RNA molecules coming from a single gene. This is called “alternative splicing”.
Alternative splicing is crucial to making sure our body has what it needs, but it’s also a mechanism that can go wrong. It’s been estimated that up to 50% of human genetic diseases are caused by mutations that affect splicing. In heritable forms of colorectal cancer, for example, it’s not unusual to find a mutation that leads to bad splicing. Imagine if an error was made when the computer printed out the architectural drawing, and the resulting plan lacked most of the foundation. A witless crew would build a mansion with no foundation. The whole thing would crumble. It would not be able to serve its original function. Likewise, a protein made from an RNA incorrectly spliced will not be able to play its role. Disease can follow.
All this talk of protein, though, and we haven’t mentioned the most fascinating aspect of RNA yet: many RNA molecules are not architectural drawings. They serve other functions.
Scientists are quickly discovering an incredibly complex ecosystem, a microcosm at the molecular level that is more intricate than we ever imagined. A cell needs to know when to build its mansions, if you will, or when to turn on its genes. This process is regulated in ways that are still being uncovered, and it involves some RNA-on-RNA action.
This is the world of non-coding RNAs, and they come in all shapes and sizes. Some of the smaller ones are known as microRNAs and they will interfere with the coding RNA on its way to being turned into a protein. You can imagine these microRNAs like Post-It notes flying in the breeze and landing on the architectural drawing, tagging it for shredding. Data suggest that between 30 and 90% of all human protein-coding genes are regulated, in part, by these microRNAs.
Longer versions of these non-coding RNAs play important roles as well. One of them even silences part of a woman’s DNA. While a man’s sex chromosomes are X and Y, a woman has X and X. The man’s Y chromosome is tiny (200 genes), whereas the X chromosome is much more massive (1,400 genes). Herein lies the problem: how can women get a similar “dose” of these X-linked genes as men when they have many more of them?
The answer is that one of their X chromosomes is silenced, and this silencing comes in the form of an RNA coating. This RNA molecule, called Xist, attaches itself to the X chromosome to be inactivated and recruits proteins that will prevent the genes underneath from making RNA and, thus, proteins. Fun fact: 12 to 20% of these genes do escape silencing.
Many more types of RNA molecules exist, such as ribosomal RNAs, which plays an essential part on the construction site of the cell, and transfer RNAs, which carry the building blocks of the protein to the construction workers erecting the structure. But more bizarre than these are circular RNA molecules, which were once thought to be errors in splicing, and which are now known as regulators of the regulators, acting as microRNA sponges!
Fundamental knowledge of these molecules and their varied roles in the cell is critical if we are to develop new technologies to improve human health. If specific RNA molecules can be associated with a particular disease state (for example, an excess of specific microRNAs in the blood), detection of these tell-tale signs could help with diagnosis, prognosis, and predicting response to treatment. Beyond human health, harnessing the power of these RNAs can positively impact our food supply. Already, small non-coding RNAs have been used to silence the gene that creates apple browning, and this technology promises to make even more significant targeted modifications to our food stock.
Yes, DNA is cool. But RNA might just be even cooler.
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