TIP60 is a cellular lysine acetyltransferase that is getting increasing attention because of its role in the regulation of gene expression, in the response of a cell to DNA damage and as a tumor suppressor. TIP60 acetylates histones and critical cellular proteins involved in DNA damage response like p53, p21 and ATM kinase. In the previous cycle of this grant we discovered that two viruses use virally encoded oncoproteins, the E6 oncoprotein from human papilloma virus (HPV) and the E1b55K+E4Orf6 oncoproteins from adenovirus, to promote the degradation of the TIP60 tumor suppressor by proteasomes. The degradation of TIP60 is important for regulating the expression of viral genes and for modulating the cell's response to DNA damage. In parallel, we discovered that a cellular deubiquitinase, USP7, stabilizes TIP60 in human cells. We now propose to investigate whether the proteasome-mediated degradation of TIP60 can be exploited for therapy.
Aim 1 will test the hypothesis that the degradation of TIP60 by HPV E6 oncoprotein is mediated by direct protein-protein interactions between TIP60 and E6, and that the degradation leads to changes in cellular gene expression, cell transformation and the susceptibility to radiotherapy of HPV-infected cells and cancers. We will also test whether stabilization of TIP60 impairs the replicative life of the virusin keratinocytes in organotypic raft cultures and thus be a potential avenue of suppressing HPV infection.
Aim 2 will test the hypothesis that adenovirus oncoproteins degrade TIP60 by harnessing specific cellular proteins to create a virus-specific E3 ubiquitin ligase, and that this degradation alters viral gene expression programs to facilitate viral replication. This project advances our novel discoveries on the degradation of TIP60 by viral oncoproteins. Success in this project will enhance our understanding of HPV-infected cancers and identify a new mechanism by which adenovirus oncoproteins de-regulate the cellular machinery to facilitate viral infection.

Public Health Relevance

Protein modifications by the TIP60 acetyltranferase are emerging as being very important for the control of cell proliferation and for the response of a cell to DNA damage. This project will enhance our understanding of how human papilloma virus (HPV) causes cancers by degrading TIP60 and why these cancers are very sensitive to radiotherapy. It will discover a new group of cellular proteins that are hijacked by a common virus of the respiratory tract, adenovirus, to degrade TIP60 for the virus's own benefit. The entir project is a great example of how blue-skies basic science grants funded by the NIH unexpectedly make discoveries that may improve the therapy of human disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Janes, Daniel E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Schools of Medicine
United States
Zip Code
Kumar, Pankaj; Anaya, Jordan; Mudunuri, Suresh B et al. (2014) Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets. BMC Biol 12:78
Negishi, Masamitsu; Wongpalee, Somsakul P; Sarkar, Sukumar et al. (2014) A new lncRNA, APTR, associates with and represses the CDKN1A/p21 promoter by recruiting polycomb proteins. PLoS One 9:e95216
Gupta, A; Jha, S; Engel, D A et al. (2013) Tip60 degradation by adenovirus relieves transcriptional repression of viral transcriptional activator EIA. Oncogene 32:5017-25
Terai, Kenta; Shibata, Etsuko; Abbas, Tarek et al. (2013) Degradation of p12 subunit by CRL4Cdt2 E3 ligase inhibits fork progression after DNA damage. J Biol Chem 288:30509-14
Jha, Sudhakar; Gupta, Ashish; Dar, Ashraf et al. (2013) RVBs are required for assembling a functional TIP60 complex. Mol Cell Biol 33:1164-74
Rosenbaum, Jean; Baek, Sung Hee; Dutta, Anindya et al. (2013) The emergence of the conserved AAA+ ATPases Pontin and Reptin on the signaling landscape. Sci Signal 6:mr1
Dar, Ashraf; Shibata, Etsuko; Dutta, Anindya (2013) Deubiquitination of Tip60 by USP7 determines the activity of the p53-dependent apoptotic pathway. Mol Cell Biol 33:3309-20
Abbas, Tarek; Keaton, Mignon; Dutta, Anindya (2013) Regulation of TGF-* signaling, exit from the cell cycle, and cellular migration through cullin cross-regulation: SCF-FBXO11 turns off CRL4-Cdt2. Cell Cycle 12:
Abbas, Tarek; Keaton, Mignon A; Dutta, Anindya (2013) Genomic instability in cancer. Cold Spring Harb Perspect Biol 5:a012914
Shibata, Yoshiyuki; Kumar, Pankaj; Layer, Ryan et al. (2012) Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues. Science 336:82-6

Showing the most recent 10 out of 18 publications