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One UNC scientist has been on a career-long quest to understand how genes are expressed as mRNAs.

Lillie Searles
Lillie Searles

As people try to get their heads around the new messenger RNA (mRNA) vaccines, the central dogma of transcription and translation is back in the headlines. The pandemic reminds us that our understanding of these key processes rests on decades of discovery science by scientists working in many fields. Indeed, many of the most innovative solutions in biomedicine are born from puzzles being solved in labs where there is no obvious application but rather simply a drive to understand the inner workings of life.

One UNC scientist’s career-long quest to understand how genes are expressed as mRNAs illustrates this well. Lillie Searles, professor of biology emeritus, led a scientific team to pursue a fundamental question that arose from genetic curiosity that ultimately led to a molecular understanding of an important aspect of gene expression in human cells.

Searles recently retired after more than three decades exploring the mechanisms by which our genes are transcribed into mRNA, identifying machinery that checks the process for errors and eliminates mRNAs that don’t meet the quality control standards. This story began in the fruit fly Drosophila, the model animal Searles started investigating as a postdoctoral fellow at Duke University and later at the National Institute of Environmental Health Sciences in Research Triangle Park in the 1980s. Her work led her into studying the effects of transposable elements.  These selfish DNA “parasites” can copy their own gene sequences and paste them into new places in the genome, sometimes interrupting the function of the genes in which they inserted.

In 1986, Searles joined UNC’s faculty and she and her lab built on her previous discoveries. They focused on a fruit fly gene called ”suppressor of sable,” Su(s).  Su(s) was first identified in 1915 by Calvin Bridges, working with one of the founders of the field of genetics, Thomas Hunt Morgan, 1933 Nobel Laureate in Physiology or Medicine. For decades, these “suppressor genes,” genes whose mutation changed the expression of other genes, remained a functional mystery, and were largely viewed as a fruit fly curiosity. However, thanks to work of Searles and others we now know that these genes are not unique to fruit flies but actually encode key parts of the core machinery that regulates gene expression.

In a series of scientific papers over 25 years funded by grants from the National Science Foundation, Searles and her team of graduate students and lab technicians gradually unveiled the mechanisms by which Su(s) acts, focusing initially on a gene called vermilion, for the effect of its loss on fruit fly eye color. Using new techniques in molecular biology, they examined how insertion of a transposable element altered expression of the vermilion gene into mRNA, and then examined how Su(s) affected this. Step-by-step, they built a more detailed picture of how Su(s) protein interacted with both DNA and mRNAs.

As new technical advances came onto the scene, they put those new techniques to work in their system, ultimately moving beyond their original Su(s) target to look at effects on mRNA transcription more broadly. With precision and focus, they methodically built a more detailed picture of Su(s) function. In their most recent papers they proposed that Su(s) was part of a protein complex that identifies mRNAs with problems and targets those mRNAs for early termination and destruction.  Finally, using new technologies, they identified a less well studied protein, Wdr82, as a partner of Su(s) in this process, and pointed out that both proteins have distant relatives in the human genome, where they might play similar roles.

Just this month, this prediction came to fruition, in an amazing capstone for the work of the Searles lab. The group of Gioacchino Natoli at the European Institute of Oncology in Milan, Italy, had been exploring the role of Wdr82 in human cells. In new work just published in Nature Structural and Molecular Biology, Natoli’s lab reports that Wdr82 forms a protein complex with Su(s)’s human homolog. This complex associates with RNA polymerase, which is the machine that transcribes mRNAs from our genes, looks for mRNAs with aberrant structures genome- wide, and terminates their transcription. Thus Su(s) and its human homolog form a key part of a new “checkpoint” that ensures aberrant mRNAs are destroyed.

A remarkable part of this story was the expression of gratitude Natoli sent to Searles when his lab’s work was under peer review.

“I should have done it long ago but I just wanted to thank you for your amazingly accurate work on Su(s) as it has been incredibly useful as well as inspiring for an entire research line in my lab, Natoli wrote. “A few years ago we stumbled upon an effect of the depletion of Wdr82 on extragenic transcription that we published in Molecular Cell without (honestly) understanding much about what was going on. When your paper on the interaction of Wdr82 with Su(s) was published in RNA in 2016, a whole new world opened up before our eyes, and I and my collaborators started reading all your old papers (from 1986 on) on the vermilion gene and the suppressive effect of Su(s). Thanks to your work, we started understanding the essential role of Wdr82 in the control of inefficiently spliced non-coding RNAs generated from enhancers and promoters in mammalian cells.”

What Natoli shared is a process that happens all the time, in which scientists make sense of the complex phenomena in human cells based on decades of work done in simpler “model” systems.

Science is a human endeavor and at its best it involves people driven by their curiosity and seeking to answer important questions about the world around us. Most often progress does not come in flashes of insight but in the steady accumulation of knowledge, with scientists building on the work of others.

Searles dedicated her scientific career to a puzzle, not knowing how her discoveries would influence the future but with conviction it was interesting and worth pursuing. So much of our understanding of cells relies on the quiet dedication of basic scientists like Searles. Let us hope there always is space for these creative and determined scientists to provide the answers to problems that still await us.

By Mark Peifer and Amy Gladfelter, professors of biology

 

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