Structural basis of O6-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein

James M. Aramini; Julie L. Tubbs; Sreenivas Kanugula; Paolo Rossi; Asli Ertekin; Melissa Maglaqui; Keith Hamilton; Colleen T. Ciccosanti; Mei Jiang; Rong Xiao; Ta Tsen Soong; Burkhard Rost; Thomas B. Acton; John K. Everett; Anthony E. Pegg; John A. Tainer; Gaetano T. Montelione

doi:10.1074/jbc.M109.093591

Structural basis of O⁶-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein

James M. Aramini, Julie L. Tubbs, Sreenivas Kanugula, Paolo Rossi, Asli Ertekin, Melissa Maglaqui, Keith Hamilton, Colleen T. Ciccosanti, Mei Jiang, Rong Xiao, Ta Tsen Soong, Burkhard Rost, Thomas B. Acton, John K. Everett, Anthony E. Pegg, John A. Tainer, Gaetano T. Montelione

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

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Abstract

Alkyltransferase-like proteins (ATLs) are a novel class of DNA repair proteins related to O⁶-alkylguanine-DNA alkyltransferases (AGTs) that tightly bind alkylated DNA and shunt the damaged DNA into the nucleotide excision repair pathway. Here, we present the first structure of a bacterial ATL, from Vibrio parahaemolyticus (vpAtl). We demonstrate that vpAtl adopts an AGT-like fold and that the protein is capable of tightly binding to O ⁶-methylguanine-containing DNA and disrupting its repair by human AGT, a hallmark of ATLs. Mutation of highly conserved residues Tyr²³ and Arg³⁷ demonstrate their critical roles in a conserved mechanism of ATL binding to alkylated DNA. NMR relaxation data reveal a role for conformational plasticity in the guanine-lesion recognition cavity. Our results provide further evidence for the conserved role of ATLs in this primordial mechanism of DNA repair.

Original language	English (US)
Pages (from-to)	13736-13741
Number of pages	6
Journal	Journal of Biological Chemistry
Volume	285
Issue number	18
DOIs	https://doi.org/10.1074/jbc.M109.093591
State	Published - Apr 30 2010

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Biology
Cell Biology

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Aramini, J. M., Tubbs, J. L., Kanugula, S., Rossi, P., Ertekin, A., Maglaqui, M., Hamilton, K., Ciccosanti, C. T., Jiang, M., Xiao, R., Soong, T. T., Rost, B., Acton, T. B., Everett, J. K., Pegg, A. E., Tainer, J. A., & Montelione, G. T. (2010). Structural basis of O⁶-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein. Journal of Biological Chemistry, 285(18), 13736-13741. https://doi.org/10.1074/jbc.M109.093591

@article{ee63678971ca471ea2aa1a32b2fa63c9,

title = "Structural basis of O6-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein",

abstract = "Alkyltransferase-like proteins (ATLs) are a novel class of DNA repair proteins related to O6-alkylguanine-DNA alkyltransferases (AGTs) that tightly bind alkylated DNA and shunt the damaged DNA into the nucleotide excision repair pathway. Here, we present the first structure of a bacterial ATL, from Vibrio parahaemolyticus (vpAtl). We demonstrate that vpAtl adopts an AGT-like fold and that the protein is capable of tightly binding to O 6-methylguanine-containing DNA and disrupting its repair by human AGT, a hallmark of ATLs. Mutation of highly conserved residues Tyr23 and Arg37 demonstrate their critical roles in a conserved mechanism of ATL binding to alkylated DNA. NMR relaxation data reveal a role for conformational plasticity in the guanine-lesion recognition cavity. Our results provide further evidence for the conserved role of ATLs in this primordial mechanism of DNA repair.",

author = "Aramini, {James M.} and Tubbs, {Julie L.} and Sreenivas Kanugula and Paolo Rossi and Asli Ertekin and Melissa Maglaqui and Keith Hamilton and Ciccosanti, {Colleen T.} and Mei Jiang and Rong Xiao and Soong, {Ta Tsen} and Burkhard Rost and Acton, {Thomas B.} and Everett, {John K.} and Pegg, {Anthony E.} and Tainer, {John A.} and Montelione, {Gaetano T.}",

year = "2010",

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doi = "10.1074/jbc.M109.093591",

language = "English (US)",

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Aramini, JM, Tubbs, JL, Kanugula, S, Rossi, P, Ertekin, A, Maglaqui, M, Hamilton, K, Ciccosanti, CT, Jiang, M, Xiao, R, Soong, TT, Rost, B, Acton, TB, Everett, JK, Pegg, AE, Tainer, JA & Montelione, GT 2010, 'Structural basis of O⁶-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein', Journal of Biological Chemistry, vol. 285, no. 18, pp. 13736-13741. https://doi.org/10.1074/jbc.M109.093591

TY - JOUR

T1 - Structural basis of O6-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein

AU - Aramini, James M.

AU - Tubbs, Julie L.

AU - Kanugula, Sreenivas

AU - Rossi, Paolo

AU - Ertekin, Asli

AU - Maglaqui, Melissa

AU - Hamilton, Keith

AU - Ciccosanti, Colleen T.

AU - Jiang, Mei

AU - Xiao, Rong

AU - Soong, Ta Tsen

AU - Rost, Burkhard

AU - Acton, Thomas B.

AU - Everett, John K.

AU - Pegg, Anthony E.

AU - Tainer, John A.

AU - Montelione, Gaetano T.

PY - 2010/4/30

Y1 - 2010/4/30

N2 - Alkyltransferase-like proteins (ATLs) are a novel class of DNA repair proteins related to O6-alkylguanine-DNA alkyltransferases (AGTs) that tightly bind alkylated DNA and shunt the damaged DNA into the nucleotide excision repair pathway. Here, we present the first structure of a bacterial ATL, from Vibrio parahaemolyticus (vpAtl). We demonstrate that vpAtl adopts an AGT-like fold and that the protein is capable of tightly binding to O 6-methylguanine-containing DNA and disrupting its repair by human AGT, a hallmark of ATLs. Mutation of highly conserved residues Tyr23 and Arg37 demonstrate their critical roles in a conserved mechanism of ATL binding to alkylated DNA. NMR relaxation data reveal a role for conformational plasticity in the guanine-lesion recognition cavity. Our results provide further evidence for the conserved role of ATLs in this primordial mechanism of DNA repair.

AB - Alkyltransferase-like proteins (ATLs) are a novel class of DNA repair proteins related to O6-alkylguanine-DNA alkyltransferases (AGTs) that tightly bind alkylated DNA and shunt the damaged DNA into the nucleotide excision repair pathway. Here, we present the first structure of a bacterial ATL, from Vibrio parahaemolyticus (vpAtl). We demonstrate that vpAtl adopts an AGT-like fold and that the protein is capable of tightly binding to O 6-methylguanine-containing DNA and disrupting its repair by human AGT, a hallmark of ATLs. Mutation of highly conserved residues Tyr23 and Arg37 demonstrate their critical roles in a conserved mechanism of ATL binding to alkylated DNA. NMR relaxation data reveal a role for conformational plasticity in the guanine-lesion recognition cavity. Our results provide further evidence for the conserved role of ATLs in this primordial mechanism of DNA repair.

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JO - Journal of Biological Chemistry

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IS - 18

ER -

Structural basis of O⁶-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein

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