Photo courtesy of Prof. Samie Jaffrey

Prof. Samie Jaffrey holds a dish containing tissue cultures used to study the methylation of mRNA.

February 6, 2017

Researchers Explain Mechanism Controlling Cell Protein Generation

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The human body is made of trillions of cells. Each fulfills a specific purpose, undergoes tremendous wear and tear and is eventually replaced. Despite extensive research, some questions related to protein production that fuels this simple process have gone unanswered. Fascinated by these intricacies, Prof. Samie Jaffrey, pharmacology, may have found part of the answer.

Jaffrey and his team discovered that messenger RNA molecules, responsible for conveying genetic information to protein producers in the cell, have special features that predetermine how much protein they generate. The discovery could provide scientists with a greater understanding of the causes of cancer and ways of regulating it.

“Over the past few years we have found that methylation [deposition of methyl groups] inside the mRNA can have effects on translation [the process of translating genetic information to physical protein production] and stability,” Jaffrey said.

Existing literature suggested that Adenosine, one of the building blocks of mRNA, could have either one or two methyl groups attached to it. Consequently, these were referred to as Am and m6Am respectively.

“What we found is that when the adenosine is dimethylated [marked by two methyl groups], the mRNA is much more stable in cells, allowing it to accumulate to high levels. Additionally, for some reason that we don’t fully understand, these mRNAs are also more efficiently translated. So, one single methyl group is enough to completely alter the fate of an mRNA inside the cell. The added stability this extra methyl group affords creates favorable conditions for higher protein expression,” Jaffrey said.

With the help of next-generation sequencing, Jaffrey surveyed all mRNA expressed by the cell for modified nucleotides, the building blocks of genetic material. This helped them recover RNA fragments that contained these nucleotides. This information, in turn, showed which mRNAs, and which parts of those mRNAs had methylated nucleotides.

Because the mRNA studied are crucial to cellular metabolism, cancer researchers searching for patterns in diseased cells could soon unravel the reasons for uncontrolled protein accumulation leading to the disease.

“We are already finding evidence that various disease states have significant reductions in the level of the dimethylated adenosine m6Am. These reductions could be very important for promoting these states. We are currently examining how these changes are linked to disease progression.”

The team also discovered that an enzyme, known as Fat Mass and Obesity Associated protein, could be used to remove the extra methyl group on m6Am. According to Jaffrey, this would have important implications in neurology.

“We know that animals that had elevated m6Am due to genetic deletion of the FTO enzyme show markedly altered brain function and significant metabolic abnormalities. This tells us that you have to have precise control of m6Am in order for proper physiological function. Researchers in these areas will now try and understand how m6Am regulates these physiological processes.”