Noncoding translation mitigation.

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Translation occurs beyond canonical coding regions, including long noncoding RNAs, untranslated regions, and introns.
• This noncanonical translation is implicated in aging, neurodegeneration, and cancer, with many tumor-specific antigens arising from it.
• Mechanisms for surveilling noncoding translation and the functional evolution of resulting polypeptides remain largely unknown.

Purpose of the Study:

• To investigate the mechanisms of noncoding translation surveillance.
• To understand how polypeptides from noncoding regions acquire new functions.
• To elucidate the biochemical pathways governing the localization of these novel polypeptides.

Main Methods:

• Integration of massively parallel analyses of over 10,000 human genomic and millions of random sequences.
• Genome-wide CRISPR screens.
• In-depth genetic and biochemical characterizations.

Main Results:

• Intrinsic nucleotide bias in the noncoding genome and genetic code often yields polypeptides with hydrophobic C-terminal tails.
• The BAG6 membrane protein triage complex captures these hydrophobic tails, directing polypeptides for degradation or membrane targeting.
• Canonical proteins have evolved to lack C-terminal hydrophobic residues, distinguishing them from noncoding translation products.

Conclusions:

• A fail-safe surveillance mechanism exists for unwanted translation from diverse noncoding genomic regions.
• This mechanism involves the BAG6 complex and hydrophobic C-terminal tail recognition.
• A potential biochemical route for the preferential membrane localization of newly evolved proteins is identified.