Flipping of alkylated DNA damage bridges base and nucleotide excision repair

Julie L. Tubbs, Vitaly Latypov, Sreenivas Kanugula, Amna Butt, Manana Melikishvili, Rolf Kraehenbuehl, Oliver Fleck, Andrew Marriott, Amanda J. Watson, Barbara Verbeek, Gail McGown, Mary Thorncroft, Mauro F. Santibanez-Koref, Christopher Millington, Andrew S. Arvai, Matthew D. Kroeger, Lisa A. Peterson, David M. Williams, Michael G. Fried, Geoffrey P. Margison, Anthony E. Pegg () and John A. Tainer ()
Additional contact information
Julie L. Tubbs: The Scripps Research Institute, La Jolla, California 92037, USA
Vitaly Latypov: Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK
Sreenivas Kanugula: Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
Amna Butt: Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK
Manana Melikishvili: Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40536, USA
Rolf Kraehenbuehl: NWCRF Institute, Bangor University
Oliver Fleck: NWCRF Institute, Bangor University
Andrew Marriott: Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK
Amanda J. Watson: Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK
Barbara Verbeek: Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK
Gail McGown: Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK
Mary Thorncroft: Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK
Mauro F. Santibanez-Koref: Institute of Human Genetics, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
Christopher Millington: Centre for Chemical Biology, University of Sheffield
Andrew S. Arvai: The Scripps Research Institute, La Jolla, California 92037, USA
Matthew D. Kroeger: The Scripps Research Institute, La Jolla, California 92037, USA
Lisa A. Peterson: University of Minnesota, Minneapolis, Minnesota 55455, USA
David M. Williams: Centre for Chemical Biology, University of Sheffield
Michael G. Fried: Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40536, USA
Geoffrey P. Margison: Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK
Anthony E. Pegg: Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
John A. Tainer: The Scripps Research Institute, La Jolla, California 92037, USA

Nature, 2009, vol. 459, issue 7248, 808-813

Abstract: Abstract Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O6-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 O6-methylguanine or cigarette-smoke-derived O6-4-(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.

Date: 2009
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DOI: 10.1038/nature08076

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