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Mol Cell Biol, March 1998, p. 1660-1669, Vol. 18, No. 3
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Implication of Localization of Human DNA Repair Enzyme O6-Methylguanine-DNA Methyltransferase at Active Transcription Sites in Transcription-Repair Coupling of the Mutagenic O6-Methylguanine Lesion

Rahmen B. Ali, Alvin K.-C. Teo, Hue-Kian Oh, Linda S.-H. Chuang, Teck-Choon Ayi, 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 May 1997/Returned for modification 27 June 1997/Accepted 27 October 1997

DNA lesions that halt RNA polymerase during transcription are preferentially repaired by the nucleotide excision repair pathway. This transcription-coupled repair is initiated by the arrested RNA polymerase at the DNA lesion. However, the mutagenic O6-methylguanine (6MG) lesion which is bypassed by RNA polymerase is also preferentially repaired at the transcriptionally active DNA. We report here a plausible explanation for this observation: the human 6MG repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is present as speckles concentrated at active transcription sites (as revealed by polyclonal antibodies specific for its N and C termini). Upon treatment of cells with low dosages of N-methylnitrosourea, which produces 6MG lesions in the DNA, these speckles rapidly disappear, accompanied by the formation of active-site methylated MGMT (the repair product of 6MG by MGMT). The ability of MGMT to target itself to active transcription sites, thus providing an effective means of repairing 6MG lesions, possibly at transcriptionally active DNA, indicates its crucial role in human cancer and chemotherapy by alkylating agents.

* 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 3797. Fax: (65) 779 1117. E-mail: mcblib{at}mcbsgs1.incb.nus.edu.sg.




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