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Molecular and Cellular Biology, October 2001, p. 7105-7114, Vol. 21, No. 20
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.
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
*
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.
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