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 Pegg, John A. Tainer, Gaetano T. Montelione

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)13736-13741
Number of pages6
JournalJournal of Biological Chemistry
Volume285
Issue number18
DOIs
StatePublished - Apr 30 2010

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Alkyl and Aryl Transferases
DNA Repair
Repair
DNA
Proteins
Vibrio parahaemolyticus
Bacterial Structures
Guanine
Mutation
Plasticity
Nucleotides
Nuclear magnetic resonance
DNA alkyltransferase

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Aramini, J. M., Tubbs, J. L., Kanugula, S., Rossi, P., Ertekin, A., Maglaqui, M., ... 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
Aramini, James M. ; Tubbs, Julie L. ; Kanugula, Sreenivas ; Rossi, Paolo ; Ertekin, Asli ; Maglaqui, Melissa ; Hamilton, Keith ; Ciccosanti, Colleen T. ; Jiang, Mei ; Xiao, Rong ; Soong, Ta Tsen ; Rost, Burkhard ; Acton, Thomas B. ; Everett, John K. ; Pegg, Anthony ; Tainer, John A. ; Montelione, Gaetano T. / Structural basis of O6-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 18. pp. 13736-13741.
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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.",
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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, A, 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

Structural basis of O6-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein. / Aramini, James M.; Tubbs, Julie L.; Kanugula, Sreenivas; Rossi, Paolo; Ertekin, Asli; Maglaqui, Melissa; Hamilton, Keith; Ciccosanti, Colleen T.; Jiang, Mei; Xiao, Rong; Soong, Ta Tsen; Rost, Burkhard; Acton, Thomas B.; Everett, John K.; Pegg, Anthony; Tainer, John A.; Montelione, Gaetano T.

In: Journal of Biological Chemistry, Vol. 285, No. 18, 30.04.2010, p. 13736-13741.

Research output: Contribution to journalArticle

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

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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