Mechanisms underlying 5’ UTR-mediated transcript regulation
Precise regulation of gene expression is fundamental for cellular function and underlies development and disease. Messenger RNA (mRNA) plays a central role in gene regulation, with untranslated regions (UTRs) acting as critical regulatory hubs.
Alterations in UTRs are implicated in a range of human diseases. Hundreds of recurrent mutations have been identified in the UTRs of cancer-related genes, and mutations within UTRs are also implicated in a variety of genetic disorders.
UTRs control gene expression by modulating mRNA abundance and translation. These functions are achieved through dynamic interactions between cis-regulatory elements (e.g., RNA binding protein (RBP) recognition motifs) and trans-acting factors (e.g., RBPs).
(2) What are the trans-acting factors that interact with these cis-regulatory elements?
(3) What are the molecular processes underpinning 5’ UTR-mediated transcript regulation?
The prevailing view is that 3' UTR regulates RNA stability, translation, and localization, while 5' UTR primarily controls translation. However, recent studies have begun to challenge this dogma by demonstrating that 5’ UTR can also modulate mRNA abundance through upstream open reading frame (uORF)-triggered nonsense-mediated decay (NMD) pathway.
While past studies have provided significant insights into the mechanisms underlying 5' UTR-mediated translational control, much less is known about how 5' UTR influences mRNA abundance.
In this project, we seek to systematically study the impact of different elements in 5’ UTR on mRNA abundance. Additionally, we are interested in identifying the key trans-acting factors that interact with these elements in 5’ UTRs. Furthermore, we are eager to discover molecular processes underpinning 5’ UTR-mediated transcript regulation.
Deciphering the mechanisms of 5’ UTR-mediated mRNA regulation will not only enhance our ability to interpret the growing number of disease-associated mutations and polymorphisms discovered in 5' UTRs, but also pave the way for improved DNA-based gene therapies and RNA therapeutics.
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Department of Pharmacology and Therapeutics
Roswell Park Comprehensive Cancer Center
Elm and Carlton Streets
Buffalo, NY 14263