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Molecular and Cellular Biology, October 2001, p. 7105-7114, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.7105-7114.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Modified Human DNA Repair Enzyme O6-Methylguanine-DNA Methyltransferase Is a Negative Regulator of Estrogen Receptor-Mediated Transcription upon Alkylation DNA Damage

Alvin K. C. Teo, Hue Kian Oh, Rahmen B. Ali, and Benjamin F. L. Li*

Chemical Carcinogenesis Laboratory, Institute of Molecular and Cell Biology, National University of Singapore, Singapore 117609, Republic of Singapore

Received 22 March 2001/Returned for modification 25 April 2001/Accepted 16 July 2001

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.

* Corresponding author. Mailing address: Chemical Carcinogenesis Laboratory, Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Dr., Singapore 117609, Republic of Singapore. Phone: (65) 874 3763 or (65) 874 3797. Fax: (65) 779 1117 or (65) 775 9582. E-mail: mcblib{at}imcb.nus.edu.sg.

Molecular and Cellular Biology, October 2001, p. 7105-7114, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.7105-7114.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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