This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tumor mutations and small DNA tumor virus proteins converge in deregulating many of the same critical cellular targets and mechanisms to drive aberrant cell proliferation. Many of the critical insights into key oncogenes and tumor suppressors pathways were first identified in studies of the small DNA tumor virus proteins. Thus, viral proteins are powerful biochemical probes to define novel cellular targets that are deregulated in cancer. Studies with DNA virus proteins have elucidated many of the critical targets and mechansims that regulate cell growth and survival and which are disrupted in human cancer, such as, p53. The degradation of p53 by cellular MDM2 and Adenovirus E1B-55k is thought to be critical for p53 inactivation in cellular and viral replication, respectively. However, recent studies from the O'Shea lab have revealed a viral protein that acts via a novel and dominant epigenetic mechanism to silence p53 activity at cellular chromatin, irrespective of p53 stabilization and phosphorylation. The de novo induction of repressive heterochromatin at p53 responsive promoters is associated with the formation of a novel nuclear matrix like structure. In collaboration with the NCMIR, the goal of this project is to elucidate the molecular features and role of this novel nuclear structure in mediating heterochromatin formation and p53 inactivation in viral and tumor replication.