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TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter. (PLoS Pathog, Oct 2017)

Rajagopalan D1,2, Pandey AK1, Xiuzhen MC1,2, Lee KK1, Hora S1,2, Zhang Y1, Chua BH1, Kwok HS1, Bhatia SS1, Deng LW2, Tenen DG1,3, Kappei D1, Jha S1,2.

Author information
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3 Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, United States of America.

Abstract
HIV1-TAT interacting protein (TIP60) is a haploinsufficient tumor suppressor. However, the potential mechanisms endowing its tumor suppressor ability remain incompletely understood. It plays a vital role in virus-induced cancers where TIP60 down-regulates the expression of human papillomavirus (HPV) oncoprotein E6 which in turn destabilizes TIP60. This intrigued us to identify the role of TIP60, in the context of a viral infection, where it is targeted by oncoproteins. Through an array of molecular biology techniques such as Chromatin immunoprecipitation, expression analysis and mass spectrometry, we establish the hitherto unknown role of TIP60 in repressing the expression of the catalytic subunit of the human telomerase complex, TERT, a key driver for immortalization. TIP60 acetylates Sp1 at K639, thus inhibiting Sp1 binding to the TERT promoter. We identified that TIP60-mediated growth suppression of HPV-induced cervical cancer is mediated in part due to TERT repression through Sp1 acetylation. In summary, our study has identified a novel substrate for TIP60 catalytic activity and a unique repressive mechanism acting at the TERT promoter in virus-induced malignancies.

PMID: 29045464


Image: Deepa Rajagopalan