Codon usage regulates human KRAS expression at both transcriptional and translational levels

Area of Science:

• Molecular Biology
• Genetics
• Cancer Biology

Background:

• KRAS and HRAS are homologous oncogenic proteins frequently mutated in human cancers.
• KRAS and HRAS exhibit distinct codon usage biases, with KRAS enriched for rare codons.

Purpose of the Study:

• To investigate the impact of KRAS and HRAS codon usage on gene expression and protein function.
• To elucidate the mechanisms by which rare codons in KRAS affect protein expression.

Main Methods:

• Utilized human cell lines expressing HRAS or KRAS.
• Performed in vitro transcription and translation assays.
• Analyzed effects of codon usage on mRNA translation efficiency, transcription rates, and protein conformation.

Main Results:

• Rare codons in KRAS significantly inhibit both translation efficiency and transcription, with varying contributions across cell lines.
• Wild-type KRAS mRNA demonstrates poor translation due to rare codons.
• Common codons enhance transcription by promoting histone modifications and coactivator recruitment.
• Codon usage influences KRAS protein conformation via co-translational folding.

Conclusions:

• Codon usage has multidimensional effects on KRAS protein expression, impacting transcription, translation efficiency, and co-translational protein folding.
• Understanding codon usage is crucial for regulating oncogenic Ras GTPase family member expression in cancer biology.