PRRC2 proteins impact translation initiation by promoting leaky scanning

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Upstream open reading frames (uORFs) regulate gene expression by influencing translation of the main open reading frame (ORF).
• Ribosomes typically scan mRNA 5' to 3', potentially halting at uORFs, thus impeding main ORF translation.
• Leaky scanning, where ribosomes bypass uORF start codons, is a key regulatory mechanism for gene expression, but factors controlling it are poorly understood.

Purpose of the Study:

• To investigate the role of PRRC2 proteins (PRRC2A, PRRC2B, PRRC2C) in translation initiation.
• To elucidate the molecular mechanisms by which PRRC2 proteins affect the translation of mRNAs containing uORFs.

Main Methods:

• Assays to determine the impact of PRRC2 proteins on translation initiation.
• Biochemical methods to study interactions between PRRC2 proteins, translation initiation factors, and preinitiation complexes.
• Ribosome profiling to assess PRRC2 enrichment on ribosomes translating uORF-containing mRNAs.

Main Results:

• PRRC2 proteins were found to bind eukaryotic translation initiation factors and preinitiation complexes.
• PRRC2 proteins are enriched on ribosomes actively translating mRNAs with uORFs.
• PRRC2 proteins were shown to promote leaky scanning past uORF start codons, enhancing the translation of uORF-containing mRNAs.

Conclusions:

• PRRC2 proteins play a significant role in promoting leaky scanning, thereby facilitating the translation of mRNAs with uORFs.
• This mechanism provides a molecular basis for understanding the physiological and pathophysiological roles of PRRC2 proteins, particularly their association with cancer.