Eukaryotic release factor 1 from Euplotes promotes frameshifting at premature stop codons in human cells

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Frameshift mutations, or indels, in coding regions significantly impact human physiology, leading to hereditary diseases and cancers.
• Current therapeutic interventions for frameshift mutations are limited, and genome editing approaches carry inherent risks.

Purpose of the Study:

• To investigate the potential of exogenous factors to enhance +1 ribosomal frameshifting in human cells.
• To assess the efficacy of Euplotes release factor 1 (Eu eRF1) in promoting frameshifting at specific sequences relevant to human diseases.

Main Methods:

• Utilized Euplotes release factor 1 (eRF1) in human cell lines.
• Analyzed frameshifting efficiency at slippery heptameric sequences.
• Examined frameshifting at premature termination sequences in the HEXA gene (Tay-Sachs disease) and GATA3 (breast cancer).

Main Results:

• Eu eRF1 enhanced +1 ribosomal frameshifting in human cells without requiring mRNA secondary structures.
• Increased frameshifting rates were observed at the HEXA gene premature termination sequence and a GATA3 frameshift mutation site.
• The study demonstrated the potential of Eu eRF1 to modulate frameshifting in disease-relevant contexts.

Conclusions:

• Exogenous factors like Eu eRF1 show promise for increasing frameshifting in human cells.
• While further optimization is needed for clinical use, Eu eRF1 represents a potential therapeutic avenue for genetic disorders and cancers driven by frameshift mutations.