Crossroads: Making Sense of Nonsense — Stop Codons in Cellular Life and Human Disease

Crossroads: Making Sense of Nonsense — Stop Codons in Cellular Life and Human Disease

My name is Michael Lawson. I’m a first-year Giannini fellow in the Puglisi Lab here at Stanford. All biological organisms use tiny molecular machines called ribosomes to orchestrate the assembly of the many proteins that are required for cellular life. To complete this complex task, ribosomes use molecules called messenger RNAs as the blueprints for protein synthesis. The information contained within these
messenger RNAs is organized in a repeating pattern referred to as codons. And based on a relationship known as the genetic code, ribosomes read these
codons to produce proteins of the proper order and length, through a process known
as translation. I’m going to skip to the end of translation, a step known as translation termination. Now I became interested in translational termination for two reasons. First, ribosomes use a set of highly-conserved protein cofactors called termination factors to halt protein synthesis at a stop codon. And despite their importance, the precise role of the various
termination factors remains unclear. These termination factors also play a
central role in recognizing and responding to premature termination
codons, which can occur through, say, a mutation that improperly introduces a stop codon in the middle of a messenger RNA. And these mutations are notably
referred to as nonsense mutations. They consequently lead to the production of incomplete proteins. And they are a common cause of many human genetic diseases. So, an understanding of translation termination would not only help to eliminate some of the most basic mechanisms of cellular life, but could also eventually yield novel therapeutics for diverse and devastating diseases, including Cystic Fibrosis, Breast-Ovarian Cancer, and Duchenne Muscular Dystrophy. Now, before we can manipulate a basic cellular process such as translation, we first need to develop a detailed understanding of how it works. The Puglisi Lab here at Stanford has made a technological breakthrough in which they’ve adapted a DNA sequencer specifically to perform single molecule
studies of translation. By attaching different color dyes to the various
termination factors. I’m able to directly observe these factors that interact with individual ribosomes halted at stop codons, which allows me to observe the
molecular choreography that leads to translation termination. Now, I’m using yeast use factors as a model system. However I expect that my findings would
have implications for human translation as well as all the key factors are conserved from yeast to humans. Now, in addition to what happens
when ribosomes encounter a properly placed stop codon, I’m particularly interested in what happens when ribosomes encounter a premature stop codon. For reasons that remain unclear, ribosomes somehow recognize these premature stop codons as problematic and initialize a specialized decay pathway, known as nonsense-mediated decay, to ensure that these troublesome transcripts are never translated again. I find this incredible. Somehow, ribosomes are performing quality-control check at stop codons. These decisions determine the fate of a
transcript. And we don’t know how this works. By attaching different color dyes not only to the termination factors, but also to other factors we know to be important for nonsense-mediated decay, I hope to learn how ribosomes distinguish between proper and premature stop codons. Now, the distinction between a proper and a premature stop codon can have life or death consequences. Roughly 11% of all heritable human diseases are caused by premature stop codons, and few treatment options exist currently for these individuals. The hope is that an understanding of translation termination and nonsense-mediated decay would eventually teach us how to trick
ribosomes to reading through these disease-causing premature stop codons, thus producing the full-length protein, and providing relief to the patient.

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