Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation–π interactions
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Alkyltransferase-like (ATL) proteins in Schizosaccharomyces pombe (Atl1) and Thermus thermophilus (TTHA1564) protect against the adverse effects of DNA alkylation damage by flagging O6-alkylguanine lesions for nucleotide excision repair (NER). We show that both ATL proteins bind with high affinity to oligodeoxyribonucleotides containing O6-alkylguanines differing in size, polarity, and charge of the alkyl group. However, Atl1 shows a greater ability than TTHA1564 to distinguish between O6-alkylguanine and guanine and in an unprecedented mechanism uses Arg69 to probe the electrostatic potential surface of O6-alkylguanine, as determined using molecular mechanics calculations. An unexpected consequence of this feature is the recognition of 2,6-diaminopurine and 2-aminopurine, as confirmed in crystal structures of respective Atl1-DNA complexes. O6-Alkylguanine and guanine discrimination is diminished for Atl1 R69A and R69F mutants, and S. pombe R69A and R69F mutants are more sensitive toward alkylating agent toxicity, revealing the key role of Arg69 in identifying O6-alkylguanines critical for NER recognition.
Oliver J. Wilkinsona, Vitaly Latypovb, Julie L. Tubbsc, Christopher L. Millingtona, Rihito Moritad,1, Hannah Blackburna, Andrew Marriottb,2, Gail McGownb, Mary Thorncroftb, Amanda J. Watsonb, Bernard A. Connollye, Jane A. Grasbya, Ryoji Masuid, Christopher A. Huntera, John A. Tainerc, Geoffrey P. Margisonb,3, and David M. Williamsa,4
Proceedings of the National Academy of Sciences
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生命科学 » 遗传学与生物信息学 » 基因表达调控与表观遗传学