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Lookup NU author(s): Dr Mauro Santibanez Koref
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Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O-6-alkylguanine-DNA alkyltransferase (AGT) and paradoxically protect cells from the biological effects of DNA alkylation damage, despite lacking the reactive cysteine and alkyltransferase activity of AGT. Here we determine Schizosaccharomyces pombe ATL structures without and with damaged DNA containing the endogenous lesion O-6-methylguanine or cigarette-smoke-derived O-6-4-(3-pyridyl)-4-oxobutylguanine. These results reveal non-enzymatic DNA nucleotide flipping plus increased DNA distortion and binding pocket size compared to AGT. Our analysis of lesion-binding site conservation identifies new ATLs in sea anemone and ancestral archaea, indicating that ATL interactions are ancestral to present-day repair pathways in all domains of life. Genetic connections to mammalian XPG (also known as ERCC5) and ERCC1 in S. pombe homologues Rad13 and Swi10 and biochemical interactions with Escherichia coli UvrA and UvrC combined with structural results reveal that ATLs sculpt alkylated DNA to create a genetic and structural intersection of base damage processing with nucleotide excision repair.
Author(s): Tubbs JL, Latypov V, Kanugula S, Butt A, Melikishvili M, Kraehenbuehl R, Fleck O, Marriott A, Watson AJ, Verbeek B, McGown G, Thorncroft M, Santibanez-Koref MF, Millington C, Arvai AS, Kroeger MD, Peterson LA, Williams DM, Fried MG, Margison GP, Pegg AE, Tainer JA
Publication type: Article
Publication status: Published
Journal: Nature
Year: 2009
Volume: 459
Issue: 7248
Pages: 808-813
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Publishing Group
URL: http://dx.doi.org/10.1038/nature08076
DOI: 10.1038/nature08076
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