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; John A. Tainer

doi:10.1038/nature08076

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. MargisonAnthony E. Pegg, John A. Tainer

Environmental Health Sciences

Research output: Contribution to journal › Article › peer-review

108 Scopus citations

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.

Original language	English (US)
Pages (from-to)	808-813
Number of pages	6
Journal	Nature
Volume	459
Issue number	7248
DOIs	https://doi.org/10.1038/nature08076
State	Published - Jun 11 2009

Bibliographical note

Funding Information:
Acknowledgements We thank C. C. Vu and J. Gong for aiding in the synthesis of O6-pobG oligomers, M. N. Boddy, J. Prudden and A. Sarker for performing genetics and biochemical experiments, G. Guenther, S. Pebernard, R. S. Williams, J. J. Perry, B. R. Chapados, M. Bjorås, D. S. Shin, K. Hitomi, C. Hitomi, E. D. Getzoff, G. Williams, S. Tsutakawa and P. K. Cooper for suggestions, and the staff at the Advanced Light Source (ALS) SIBYLS beamline and the Stanford Synchrotron Radiation Laboratory (SSRL). Operations at SSRL and ALS are supported by the US Department of Energy and NIH. This work was supported by National Institutes of Health grants CA097209 (J.A.T., A.E.P.), CA018137 (A.E.P.), GM070662 (M.G.F.), and CA59887 (L.A.P.), The Skaggs Institute for Chemical Biology (J.L.T.), North West Cancer Research Fund grant CR675 (O.F.), Cancer Research-UK (G.P.M.) and CHEMORES (G.P.M.).

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Tubbs, J. L., Latypov, V., Kanugula, S., Butt, A., Melikishvili, M., Kraehenbuehl, R., Fleck, O., Marriott, A., Watson, A. J., Verbeek, B., McGown, G., Thorncroft, M., Santibanez-Koref, M. F., Millington, C., Arvai, A. S., Kroeger, M. D., Peterson, L. A., Williams, D. M., Fried, M. G., ... Tainer, J. A. (2009). Flipping of alkylated DNA damage bridges base and nucleotide excision repair. Nature, 459(7248), 808-813. https://doi.org/10.1038/nature08076

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 2009, 'Flipping of alkylated DNA damage bridges base and nucleotide excision repair', Nature, vol. 459, no. 7248, pp. 808-813. https://doi.org/10.1038/nature08076

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title = "Flipping of alkylated DNA damage bridges base and nucleotide excision repair",

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.",

author = "Tubbs, {Julie L.} and Vitaly Latypov and Sreenivas Kanugula and Amna Butt and Manana Melikishvili and Rolf Kraehenbuehl and Oliver Fleck and Andrew Marriott and Watson, {Amanda J.} and Barbara Verbeek and Gail McGown and Mary Thorncroft and Santibanez-Koref, {Mauro F.} and Christopher Millington and Arvai, {Andrew S.} and Kroeger, {Matthew D.} and Peterson, {Lisa A.} and Williams, {David M.} and Fried, {Michael G.} and Margison, {Geoffrey P.} and Pegg, {Anthony E.} and Tainer, {John A.}",

note = "Funding Information: Acknowledgements We thank C. C. Vu and J. Gong for aiding in the synthesis of O6-pobG oligomers, M. N. Boddy, J. Prudden and A. Sarker for performing genetics and biochemical experiments, G. Guenther, S. Pebernard, R. S. Williams, J. J. Perry, B. R. Chapados, M. Bjor{\aa}s, D. S. Shin, K. Hitomi, C. Hitomi, E. D. Getzoff, G. Williams, S. Tsutakawa and P. K. Cooper for suggestions, and the staff at the Advanced Light Source (ALS) SIBYLS beamline and the Stanford Synchrotron Radiation Laboratory (SSRL). Operations at SSRL and ALS are supported by the US Department of Energy and NIH. This work was supported by National Institutes of Health grants CA097209 (J.A.T., A.E.P.), CA018137 (A.E.P.), GM070662 (M.G.F.), and CA59887 (L.A.P.), The Skaggs Institute for Chemical Biology (J.L.T.), North West Cancer Research Fund grant CR675 (O.F.), Cancer Research-UK (G.P.M.) and CHEMORES (G.P.M.).",

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AU - Tubbs, Julie L.

AU - Latypov, Vitaly

AU - Kanugula, Sreenivas

AU - Butt, Amna

AU - Melikishvili, Manana

AU - Kraehenbuehl, Rolf

AU - Fleck, Oliver

AU - Marriott, Andrew

AU - Watson, Amanda J.

AU - Verbeek, Barbara

AU - McGown, Gail

AU - Thorncroft, Mary

AU - Santibanez-Koref, Mauro F.

AU - Millington, Christopher

AU - Arvai, Andrew S.

AU - Kroeger, Matthew D.

AU - Peterson, Lisa A.

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AU - Fried, Michael G.

AU - Margison, Geoffrey P.

AU - Pegg, Anthony E.

AU - Tainer, John A.

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N2 - 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.

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Flipping of alkylated DNA damage bridges base and nucleotide excision repair

Abstract

Bibliographical note

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