Open AccessTIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter
Author(s) -
Deepa Rajagopalan,
Amit Kumar Pandey,
Magdalene Claire Xiuzhen,
Kwok Kin Lee,
Shainan Hora,
Yanzhou Zhang,
Boon Haow Chua,
Hui Si Kwok,
Shreshtha Sailesh Bhatia,
LihWen Deng,
Daniel G. Tenen,
Dennis Kappei,
Sudhakar Jha
Publication year - 2017
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1006681
Subject(s) - chromatin immunoprecipitation , telomerase , biology , context (archaeology) , suppressor , cancer research , chromatin remodeling , immunoprecipitation , protein subunit , telomerase reverse transcriptase , psychological repression , histone , microbiology and biotechnology , promoter , cancer , genetics , gene expression , cell culture , dna , gene , paleontology
HIV1-TAT interactive 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.