Translation readthrough mitigation.

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Ribosomes can fail to terminate translation at stop codons, leading to aberrant C-terminal protein extensions.
• These extended proteins can disrupt cellular functions, and existing surveillance mechanisms are insufficient to prevent their accumulation.
• This poses a risk of dominant negative effects on cellular processes.

Purpose of the Study:

• To investigate cellular mechanisms that prevent the accumulation of C-terminal-extended proteins resulting from translation termination failures.
• To determine the role of 3′ untranslated regions (UTRs) in mitigating these translation errors.
• To explore the conservation of these mechanisms across species, including humans.

Main Methods:

• Utilized transgenics and CRISPR–Cas9 gene editing in *Caenorhabditis elegans*.
• Measured mRNA levels and translation rates to elucidate the mechanism of action.
• Performed tissue culture assays in human cells to assess the function of human 3′ UTR sequences.

Main Results:

• Demonstrated that 3′ UTR sequences effectively reduce the levels of C-terminal-extended proteins in *C. elegans*.
• Evidence suggests a co- or post-translational mechanism for 3′ UTR-mediated regulation.
• Observed similar protein-reducing effects of translated human 3′ UTR sequences in human cells, including those from a known hemoglobin variant.

Conclusions:

• 3′ untranslated regions (UTRs) play a crucial role in preventing the accumulation of proteins with aberrant C-terminal extensions due to translation termination failures.
• These UTRs likely encode peptide sequences that destabilize the resulting aberrant proteins, acting as a protective mechanism against diverse translation errors.
• The findings reveal a conserved cellular strategy for mitigating the negative consequences of translational errors in both *C. elegans* and human cells.