A single gene encodes a single protein – it was the conventional understanding for gene expression. But researchers from university of Chicago found a single gene to express two separate proteins from the same mRNA sequence. This study can change existing concept of translation process. This new mechanism of gene expression might develop new strategies for untreatable neurological diseases.
This finding was published in online journal Cell on 3 July.
Leader of study team, Christopher Gomez said that it was the first observation in eukaryotic organism to produce multiple proteins from single mRNA at the same time. He said, ““It represents a paradigm shift in our understanding of how genes ultimately encode proteins.”
Human genome contains about 20,000 protein encoding genes. Individual genes can produce multiple mRNA sequences by changing Open Reading Fragments (ORFs). Thus based on position of reading fragments, multiple proteins can be produced.
But the study team discovered a more complex mechanism of gene expression. They studied on a neurodegenerative disease – spinocerebellar ataxia type-6 (SCA6). Patients suffering from this disease slowly lose co-ordination of their muscles and eventually lose ability to speak and stand. The cause of this disease is due to a mutation in CACNA1A gene – a gene encoding a calcium channel protein. Channel proteins are vital for signaling of nerve cells. A mutation in CACNA1A gene produces extra copies of glutamine.
Though scientists knew the gene and its effect due to mutation, biological mechanism of the disease were obscure to them. The mutation does not hamper the function of Calcium Channel protein. Gomez and his team suspected another protein – α1ACT. Scientists later found this protein to be a free fragment of CACNA1A calcium channel protein. This fragment is known to produce extra copies of glutamine in SCA6 cells. Surprisingly, α1ACT was originated from the same mRNA sequence as the calcium channel protein.
This is the first evidence that a strand of mRNA transcribed two structurally separated proteins simultaneously. This happened due to a special sequence named internal ribosomal entry site (IRES). Generally they are found in the beginning of mRNA strand. But here, IRES located in the middle position of mRNA, thus created second location for ribosomes to read mRNA. Two separate MRNA reading produced two separate proteins.
The functions of α1ACT are to act as transcription factor and to enhance growth of particular brain cells. A notable point is the mutation in α1ACT proves to be toxic for nerve cells in vitro. Mutation also caused SCA6-like symptoms in animal cells.
The team is trying to understand the functionality of such “bifunctional” genes. The location of IRES has significance role in protein production, as this discovery suggests. Now they are working on SCA6 patients to remove problems of mutated α1ACT.
“We discovered these genetic phenomena in pursuit of a disease. After finding it, we have a potential strategy to develop preclinical tools to treat that disease,” Gomez said. He hopes that, targeted action on IRES to inhibit production of mutated α1ACT, might prevent development of neurological diseases.