Oncogenic Functions Of The Saga Complex

Our research is focused on defining the functions of histone modifying enzymes in normal cells, so that we can understand how alterations in these activities contribute to tumor development or progression. Many of our studies focus on the SAGA complex, which houses both histone acetyltransferase (HAT; Gcn5) and deubiquitylase (DUB; USP22) activities, as well as core module that has features resembling both the histone octamer and TFIID. In an effort to dissect the roles of these modules in SAGA, we have made mice bearing mutations in GCN5, including a deletion allele, a mutant hat mutant allele, and a mutant bromodomain allele. We have also created mice null for USP22 and mice that overexpress this DUB. Our data revealed that Gcn5 is an important co-activator for Myc in regulating self-renewal of mouse ES cells, as a Yamanaka factor in stimulating conversion of differentiated cells towards an induced pluripotent state, and as an oncogene. The SAGA DUB module is also implicated in cancer, as the USP22 catalytic subunit is overexpressed in several highly aggressive human tumors. Our data indicate that USP22 drives TGF-beta and receptor tyrosine kinase signaling pathways that are critical both to normal developmental processes and to oncogenesis. Altogether, our studies indicate that both Gcn5 and USP22 may provide unique targets for development of new cancer therapies.