It has recently become clear that various aspects of nucleic acid metabolism and the ubiquitin-proteasome pathway intersect in several direct and important ways. To begin to assess the scope of some of these activities in the yeast Saccharomyces cerevisiae, we assessed the physical and functional association of proteasomal proteins from both the 20 S core and 19 S regulatory particles with approximately 6400 yeast genes. Genome-wide chromatin immunoprecipitation analyses revealed that proteasome substituents are associated with the majority of yeast genes. Many of these associations correlated strongly with expression levels and the presence of RNA polymerase II. Although the data support the presence of the intact 26 S proteasome on most genes, several hundred yeast genes were cross-linked to either the 20 or 19 S complex but not both, consistent with some degree of independent function for the proteasomal subcomplexes.