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Study: Yi-Tao Yu, Paul Boutz Harness Power, Precision of RNA to Make Mutations Invisible

Monday, March 6, 2023

Scientists have discovered a new way to suppress mutations that lead to a wide range of genetic disorders. A study in the journal Molecular Cell describes a strategy that co-opts a normal RNA modification process within cells to transform disease genes into normal genes that produce healthy proteins. The findings are significant because they may ultimately help researchers alter the course of devastating disorders such as cystic fibrosis, muscular dystrophy and many forms of cancer.

Negating Nonsense

Around 15 percent of mutations that lead to genetic diseases are called nonsense mutations. Aptly named, nonsense mutations occur when an mRNA molecule contains an early “stop” signal. When the mRNA takes genetic instructions from DNA to create a protein, this early stop sign orders the cell to stop reading the instructions partway through the process. This results in the creation of an incomplete protein that can lead to disease.

Led by Yi-Tao Yu, PhD, a team of researchers from the University of Rochester Center for RNA Biology designed an artificial guide RNA – a piece of RNA that can modify other types of RNA – to target mRNA molecules that contain early stop signals (also called premature termination codons). Guide RNAs are a natural mechanism that cells use all the time; Yu’s team altered this already existing process.

Like DNA, RNA is made up of molecular building blocks that are represented by the letters A (adenine), G (guanine), U (uracil), and C (cytosine). Premature termination codons always have the building block U in the first position (for example, UAG, UAA or UGA). The team’s artificial guide RNA was designed to modify the U in the first position, changing the molecular makeup of the targeted mRNA so that the stop signal is no longer – or less well – recognized by the cell.