The Searle Scholars Program has awarded a $300,000 research grant to Joshua Arribere, assistant professor of molecular, cell, and developmental biology at UC Santa Cruz. Arribere, who studies quality control mechanisms used by cells to detect and remove mistakes in gene expression, is one of 15 young scientists to receive the prestigious awards this year.
The Searle Scholars Program makes grants to selected universities and research centers to support the independent research of exceptional young faculty in the biomedical sciences and chemistry. The program supports high-risk, high-reward research across a broad range of scientific disciplines.
Arribere studies how cells detect abnormal gene expression and protect themselves from its deleterious effects. Failure or inappropriate activation of these quality control mechanisms have been implicated in a wide range of genetic diseases, including some types of muscular dystrophies, Parkinson's disease, and hypothyroidism.
The Searle funding will support Arribere's research focusing on a pathway called "nonsense-mediated decay" (NMD), which identifies and removes errors that prematurely stop protein synthesis, resulting in truncated proteins. These errors occur when the messenger RNA carrying the genetic code for the protein includes a premature "stop codon."
Researchers have found that at least 11 percent of all human genetic diseases, and perhaps as many as 60 percent, are caused by a mutation that introduces a premature stop codon. In addition, it is thought that every person has in their cells about 120 genes that produce messenger RNAs containing premature stop codons that are silenced by nonsense-mediated decay.
"With those mutations, the messenger RNA produces an abnormally short protein, so the cell attacks the messenger RNA and gets rid of it. But there is no consensus on how this happens," Arribere said.
His lab recently discovered what appears to be a key step in this process in which a ribosome (the molecular machine that synthesizes proteins in all cells) gets stuck on a stop codon, and the messenger RNA gets attacked on the ribosome by the NMD pathway and cut at the stop codon. Based on these findings, Arribere has proposed a new model for nonsense-mediated decay, which his lab will evaluate in an effort to resolve long-standing questions.
"This pathway has been known for decades, and there are a lot of ideas about how it might work, but no agreement," he said. "A better understanding of these processes could help us to predict the effects of genetic mutations much more accurately."
Arribere earned his B.A. in applied mathematics and molecular and cellular biology at UC Berkeley and his Ph.D. in biology at the Massachusetts Institute of Technology. After a postdoctoral position at Stanford University School of Medicine, he joined the UCSC faculty in 2017.
