PHILADELPHIA (August 31, 2022)—Researchers at Fox Chase Cancer Center co-authored a multi-institutional study that found that an RNA modification enzyme is critical for the survival of motor neurons. The scientists say the findings could help in the development of new treatments for neurological and other aging-related disorders, including cancer.
Lu Chen, PhD, the corresponding author for the study, is an assistant professor in the Cancer Signaling and Epigenetics research program and a member of the Cancer Epigenetics Institute at Fox Chase. His lab seeks to establish how molecular details underlying RNA structure, localization, and chemical modifications can be harnessed to combat cancer and aging, with a long-term goal of developing RNA therapeutics.
RNA modification pathways and how to harness them as effective drugs are hot topics in the growing field of RNA transcriptomics, which has attracted a great deal of attention from both academia and the pharmaceutical industry.
Part of this buzz is due to the connection between RNA and cancer. Major cancer hallmarks, including epigenetic reprogramming, deregulating metabolism, and evasion of immune destruction are associated with what Chen called a “treasure chest” of cancer-specific RNA misregulations that can be exploited for cancer treatments and cancer biomarkers.
For this particular study, the researchers looked at TGS, an RNA-modifying enzyme that adds chemical groups onto the beginning end or “5’ cap” of RNA. Transcribed from the genetic blueprint, RNA not only serves as a messenger molecule that guides protein production but also can carry on protein-like functions itself. One type of RNA, small nuclear RNA (snRNA), forms the core of the “spliceosome,” an essential cellular machinery that “cuts” and “pastes” segments of messenger RNA, thus ensuring its accurate translation into cellular structure and function.
The researchers were able to show that loss of TGS1 leads to an accumulation of misprocessed snRNAs that retain an extended 3’ end tail, including a string of un-templated uridines, another RNA modification commonly found in immature RNAs or short-lived “junk” RNAs. These problematic snRNAs show altered cellular localization and ultimately precipitate transcriptome-wide RNA mis-splicing.
Chen said the key finding of the paper was that they uncovered an snRNA biogenesis pathway that relies on the crosstalk or coupling between two RNA modification steps at both 5’ and 3’ ends of RNA. “Such a mechanism apparently is evolutionarily conserved and protects motor neurons from premature death.”
In three model organisms—worms, flies, and zebrafish—TGS1 deficiency resulted in diminished motor neuron count, developmental defect, and loss of locomotion. These phenotypes are shared with Spinal Muscular Atrophy (SMA), a human motor neuron degenerative disorder that is a major cause of death in infancy, impacting every one in 6000 infants.
Neuron axons travel a long physical distance before reaching peripheral muscle cells, which in turn secrete neurotrophic factors that promote neuronal survival. The proper targeting of axons depends on timely and accurate execution of alternative RNA splicing, often split-second events that dictate the survival or death of a neuron.
“Our paper reinforces the theory that TGS1-deficient neurons are particularly fragile due to their defective snRNA biogenesis and spliceosome function,” Chen said. “Therapeutic boosting of TGS1 may alleviate motor neuron loss in SMA patients.”
Another Fox Chase author on the study was Marie A. “Masha” Kobin, a member of the most recent class of the Jeanne E. and Robert F. Ozols Undergraduate Summer Research Fellows, a program that is directed by Eileen K. Jaffe, PhD, a professor in the Molecular Therapeutics research program. Kobin successfully presented her results in a trainee forum hosted by the Cancers Epigenetics Institute before returning to her pursuit of a bachelor’s degree in biochemistry at Cornell University.
The study, “TGS1 Impacts snRNA 3’ End Processing, Ameliorates SMN-Dependent Neurological Phenotypes in Vivo and Prevents Neurodegeneration,” was published in Nucleic Acids Research.