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UTSW researchers reveal how frameshifting is key to SARS-CoV-2 replication

Illustration of novel coronavirus
(Photo Credit: Getty Images)

DALLAS – Sept. 01, 2023 – Researchers at UT Southwestern Medical Center discovered how the virus responsible for COVID-19 harnesses a feature of its host cells to read its genetic code twice.

This system, called programmed ribosomal frameshifting, enables the SARS-CoV-2 virus to efficiently pack its RNA in a small space, enhancing its ability to spread. Since frameshifting is used by several other viruses, including the human immunodeficiency virus (HIV) and West Nile virus, a better understanding of this process may enhance our understanding of other viral diseases beyond COVID-19.

Joshua Mendell, M.D., Ph.D.
Joshua Mendell, M.D., Ph.D., is Professor of Molecular Biology and holds the Charles Cameron Sprague, M.D. Chair in Medical Science.

“Imagine a ticker tape has a knot,” said Joshua Mendell, M.D., Ph.D., Professor of Molecular Biology, a Howard Hughes Medical Institute Investigator, and senior author of the study published in Cell Reports. “Instead of stopping at the knot, the tape reader backs up, unties the knot, and then continues reading the information.”

In the cell, the “tape reader” is the ribosome, a structure that translates the genetic code, written in the language of RNA, to construct proteins. RNA is composed of four bases. Each combination of three consecutive RNA bases codes for a single amino acid, the building block of proteins. Some of these triplet combinations – called codons – serve as signals for the ribosomes to start or stop.

Normally, ribosomes read the RNA three bases at a time – codon by codon – as they assemble the protein. Upon reaching the end of the protein-coding sequence, the ribosome releases the protein chain. An enzyme called ABCE1 then splits the ribosome in two, and the cell recycles the two subunits.

But RNA from SARS-CoV-2 contains a complicated hairpin turn that triggers frameshifting, a process in which the ribosome changes the sequence of codons that it is reading. This frameshifting event must occur to produce the proteins that replicate the SARS-CoV-2 virus, and it is therefore a critical step in the viral life cycle.

To better understand this frameshifting event, Dr. Mendell and his colleagues isolated the hairpin section and added RNA that coded for red and green fluorescent proteins. The green protein would appear only if ribosomal frameshifting happened.

They then introduced this modified RNA into human cells and knocked out every gene in the human genome, one at a time, using CRISPR gene editing. They found that frameshifting required the ribosome-splitting enzyme ABCE1. Further experiments demonstrated that if a ribosome fails to undergo frameshifting and encounters the “stop” codon, it must be very quickly removed by ABCE1 or the next ribosome in line will be unable to frameshift.

In collaboration with John Schoggins, Ph.D., Professor of Microbiology, the researchers demonstrated that inhibiting ABCE1 prevents replication of the SARS-CoV-2 virus. Therefore, this ribosome “recycling” step performed by ABCE1 could, in theory, be targeted to reduce viral infection.

Frederick Rehfeld, Ph.D.
Frederick Rehfeld, Ph.D., is Assistant Instructor of Molecular Biology.

“Frameshifting must happen to translate the virus’s entire genome,” said Frederick Rehfeld, Ph.D., Assistant Instructor of Molecular Biology and lead author of the study. “It thus provides a vulnerability that could be exploited with therapeutics that target this process.”

Dr. Mendell holds the Charles Cameron Sprague, M.D. Chair in Medical Science. Dr. Schoggins holds the Tom and Charlene Marsh Family Distinguished Chair in Medicine and Science and is a Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in Honor of Dr. Bill S. Vowell.

Other UTSW researchers who contributed to the study include Tsung-Cheng Chang, Ph.D., Assistant Professor of Molecular Biology, and Jennifer L. Eitson, Senior Research Associate.

The research was funded by grants from the National Institutes of Health (DP1AI158124), the Cancer Prevention and Research Institute of Texas (RP220309), The Welch Foundation (I-1961-20210327), and the Hamon Center for Regenerative Science and Medicine at UT Southwestern.

About UT Southwestern Medical Center 
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 19 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.