This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The long-term goal of our work is to understand the mechanism behind the development of morbidity and mortality in infants congenitally infected with human cytomegalovirus (HCMV). In the last 7 years we have shown that HCMV interacts with the key cell cycle regulatory protein p53 and sequesters it, and several key DNA damage proteins, within the viral replication centers. We have recently shown that this sequestration is dependent upon an intact DNA binding domain on the p53 protein and have found 21 consensus binding sites for p53 within the viral genome. These facts have led us to hypothesize that p53 may be recruited as a transcription factor by the virus. We have also observed very early colocalization of the p53 protein with input viral DNA. Coupled with the observations we have made in p53 knockout cells, which show dramatic decreases in viral titers, delays and decreases in viral DNA replication and delays in viral protein expression, we believe that p53 plays important roles at both early and late times post infection with HCMV. It is the major focus of this proposal to ascertain these active roles. We propose three specific aims to accomplish this goal.
AIM 1 is an investigation of the immediate early activation of p53 by HCMV infection.
AIM 2 will determine the role of p53 in viral circularization at early times post infection.
AIM 3 is a determination of the role of p53 as transcriptional activator for viral gene expression. We believe that elucidating the interactions with the key cell cycle regulator p53 may aid in our understanding of the development of the central nervous system manifestations observed in the congenitally infected infant.
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