Please use this identifier to cite or link to this item: https://doi.org/10.1128/MCB.21.20.7105-7114.2001
Title: The modified human DNA repair enzyme O6-methylguanine-DNA methyltransferase is a negative regulator of estrogen receptor-mediated transcription upon alkylation DNA damage
Authors: Teo, A.K.C. 
Oh, H.K.
Ali, R.B.
Li, B.F.L. 
Issue Date: 2001
Citation: Teo, A.K.C., Oh, H.K., Ali, R.B., Li, B.F.L. (2001). The modified human DNA repair enzyme O6-methylguanine-DNA methyltransferase is a negative regulator of estrogen receptor-mediated transcription upon alkylation DNA damage. Molecular and Cellular Biology 21 (20) : 7105-7114. ScholarBank@NUS Repository. https://doi.org/10.1128/MCB.21.20.7105-7114.2001
Abstract: Cell proliferation requires precise control to prevent mutations from replication of (unrepaired) damaged DNA in cells exposed spontaneously to mutagens. Here we show that the modified human DNA repair enzyme O6-methylguanine-DNA methyltransferase (R-MGMT), formed from the suicidal repair of the mutagenic O6-alkylguanine (6RG) lesions by MGMT in the cells exposed to alkylating carcinogens, functions in such control by preventing the estrogen receptor (ER) from transcription activation that mediates cell proliferation. This function is in contrast to the phosphotriester repair domain of bacterial ADA protein, which acts merely as a transcription activator for its own synthesis upon repair of phosphotriester lesions. First, MGMT, which is constitutively present at active transcription sites, coprecipitates with the transcription integrator CREB-binding protein CBP/p300 but not R-MGMT. Second, R-MGMT, which adopts an altered conformation, utilizes its exposed VLWKLLKVV peptide domain (codons 98 to 106) to bind ER. This binding blocks ER from association with the LXXLL motif of its coactivator, steroid receptor coactivator-1, and thus represses ER effectively from carrying out transcription that regulates cell growth. Thus, through a change in conformation upon repair of the 6RG lesion, MGMT switches from a DNA repair factor to a transcription regulator (R-MGMT), enabling the cell to sense as well as respond to mutagens. These results have implications in chemotherapy and provide insights into the mechanisms for linking transcription suppression with transcription-coupled DNA repair.
Source Title: Molecular and Cellular Biology
URI: http://scholarbank.nus.edu.sg/handle/10635/112124
ISSN: 02707306
DOI: 10.1128/MCB.21.20.7105-7114.2001
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