TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter.
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)...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-10-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1006681 |
| _version_ | 1819260799274713088 |
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| author | Deepa Rajagopalan Amit Kumar Pandey Magdalene Claire Xiuzhen Kwok Kin Lee Shainan Hora Yanzhou Zhang Boon Haow Chua Hui Si Kwok Shreshtha Sailesh Bhatia Lih Wen Deng Daniel G Tenen Dennis Kappei Sudhakar Jha |
| author_facet | Deepa Rajagopalan Amit Kumar Pandey Magdalene Claire Xiuzhen Kwok Kin Lee Shainan Hora Yanzhou Zhang Boon Haow Chua Hui Si Kwok Shreshtha Sailesh Bhatia Lih Wen Deng Daniel G Tenen Dennis Kappei Sudhakar Jha |
| author_sort | Deepa Rajagopalan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T19:31:39Z |
| format | Article |
| id | doaj.art-86fa83761c404e7ba91c24d10fb65276 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-23T19:31:39Z |
| publishDate | 2017-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-86fa83761c404e7ba91c24d10fb652762022-12-21T17:33:53ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-10-011310e100668110.1371/journal.ppat.1006681TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter.Deepa RajagopalanAmit Kumar PandeyMagdalene Claire XiuzhenKwok Kin LeeShainan HoraYanzhou ZhangBoon Haow ChuaHui Si KwokShreshtha Sailesh BhatiaLih Wen DengDaniel G TenenDennis KappeiSudhakar JhaHIV1-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.https://doi.org/10.1371/journal.ppat.1006681 |
| spellingShingle | Deepa Rajagopalan Amit Kumar Pandey Magdalene Claire Xiuzhen Kwok Kin Lee Shainan Hora Yanzhou Zhang Boon Haow Chua Hui Si Kwok Shreshtha Sailesh Bhatia Lih Wen Deng Daniel G Tenen Dennis Kappei Sudhakar Jha TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter. PLoS Pathogens |
| title | TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter. |
| title_full | TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter. |
| title_fullStr | TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter. |
| title_full_unstemmed | TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter. |
| title_short | TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter. |
| title_sort | tip60 represses telomerase expression by inhibiting sp1 binding to the tert promoter |
| url | https://doi.org/10.1371/journal.ppat.1006681 |
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