Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation.

Precise control of protein degradation is critical for life, yet how natural genetic variation affects this essential process is largely unknown. Here, we developed a statistically powerful mapping approach to characterize how genetic variation affects protein degradation by the ubiquitin-proteasome system (UPS). Using the yeast <i>Saccharomyces cerevisiae</i>, we systematically mapped genetic influences on the N-end rule, a UPS pathway in which protein N-terminal amino acids function as degradation-promoting signals. Across all 20 possible N-terminal amino acids, we identified 149 genomic loci that influence UPS activity, many of which had pathway- or substrate-specific effects. Fine-mapping of four loci identified multiple causal variants in each of four ubiquitin system genes whose products process (<i>NTA1</i>), recognize (<i>UBR1</i> and <i>DOA10</i>), and ubiquitinate (<i>UBC6</i>) cellular proteins. A <i>cis</i>-acting promoter variant that modulates UPS activity by altering <i>UBR1</i> expression alters the abundance of 36 proteins without affecting levels of the corresponding mRNA transcripts. Our results reveal a complex genetic basis of variation in UPS activity.