The life and times of an mRNA molecule

There’s a lot more happening in your cells than you might think. In a paper published online April 24 in the journal Nature Biotechnology, a team of Broad researchers describe a new technique that allows them to peer into the world of messenger RNA (mRNA), the molecule that carries the instructions for creating a protein to the site where proteins are made. Without mRNA, a gene's instructions will never be translated into a product. But, as we wrote in a press release about the paper, there’s a lot more to the life of an mRNA molecule than carrying a message. Researchers are beginning to piece together snapshots taken at short intervals to see what processes control how much mRNA exists in a cell, but here we’ll zoom in on the life of just one molecule.

The mRNA molecule we’ll be following begins its brief life with transcription, the process by which it is copied from DNA (you can watch a cool video of this process on the HHMI website). A piece of molecular machinery known as RNA polymerase sits on a strand of DNA and begins stringing together, one base pair at a time, a copy of the sequence in the four-letter language of RNA – A, C, G, and U. Soon, an RNA molecule is born. This nascent molecule is termed “pre-mRNA” – it still has a lot of growing up to do.

Before it is considered “mature mRNA,” the molecule needs to be refined and edited. First, a “cap” is added to the front end of the pre-mRNA. This cap plays a critical role in RNA’s life – it protects the molecule from RNases, enzymes that would otherwise break the molecule down, and it also helps RNA dock to the ribosome, the cellular subunit where proteins are created.

Next, RNA is “spliced,” meaning that certain non-protein-coding stretches are cut out of the molecule. In some cases, the same mRNA molecule can be spliced in more than one way, leading to slightly different messages (this means that one gene can actually code for many different proteins).

Finally, the mRNA molecule gets a tail. A string of adenine bases (As) are attached to the end of the molecule (a process called polyadenylation). Over time, this tail gets shorter and shorter. When it is short enough, the molecule will meet its end…but more on that later.

Our now fully mature, capped, spliced, and polyadenylated mRNA molecule is ready to leave its childhood home of the nucleus and set out into the cytoplasm. When it meets a free-floating ribosome in the cytoplasm, the ribosome will set about translating the mRNA’s message into a protein (another cool HHMI video can be found here).

In humans, some mRNAs live for minutes while others live for days. The longer a molecule is around, the more of its encoded protein will be produced. When the mRNA molecule’s tail grows short and its message is no longer being translated, it is time for the molecule to be destroyed – enzymes break it down. (There are plenty of other ways to stop RNA’s signal – microRNAs, small interfering RNAs (siRNAs), and more, some of which are used by the Broad’s RNAi Platform).

Cells can adjust the rates of mRNA creation and destruction, giving them a lot of control over which proteins (and how much of these proteins) are created. Broad researchers took a close look at the interplay between creation and destruction, and even got a look at some of the steps in between, by refining a lab technique and coupling it with very accurate RNA sequencing and analysis. They hope that this work will enable researchers studying diseases like cancer, diabetes, and more to look at what happens when a mutation alters one of the steps in this delicate process.