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FOR THE RECORD

Active-site alkylation destabilizes human O⁶-alkylguanine DNA alkyltransferase

¹ Departments of Biochemistry and Molecular Biology and
² Cell and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA

Reprint requests to: Michael G. Fried, Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA; e-mail: mfried{at} psu.edu; fax: (717) 531-7072.

O⁶-alkylguanine-DNA alkyltransferase (AGT) repairs pro-mutagenic O⁶-alkylguanine and O⁴-alkylthymine lesions in DNA. The alkylated form of the protein is not reactivated; instead, it is rapidly ubiquitinated and degraded. Here, we show that alkylation destabilizes the native fold of the protein by 0.5–1.2 kcal/mole and the DNA-binding function by 0.8–1.4 kcal/mole. On this basis, we propose that destabilization of the native conformational ensemble acts as a signal for ubiquitination.

Keywords: O⁶-alkylguanine-DNA alkyltransferase; O⁶-methylguanine-methyltransferase; DNA binding; denaturation; protein-alkylation

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