DNA binding, nucleotide flipping, and the helix-turn-helix motif in base repair by O6-alkylguanine-DNA alkyltransferase and its implications for cancer chemotherapy

Julie L. Tubbs, Anthony Pegg, John A. Tainer

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

O6-Alkylguanine-DNA alkyltransferase (AGT) is a crucial target both for the prevention of cancer and for chemotherapy, since it repairs mutagenic lesions in DNA, and it limits the effectiveness of alkylating chemotherapies. AGT catalyzes the unique, single-step, direct damage reversal repair of O6-alkylguanines by selectively transferring the O6-alkyl adduct to an internal cysteine residue. Recent crystal structures of human AGT alone and in complex with substrate DNA reveal a two-domain α/β fold and a bound zinc ion. AGT uses its helix-turn-helix motif to bind substrate DNA via the minor groove. The alkylated guanine is then flipped out from the base stack into the AGT active site for repair by covalent transfer of the alkyl adduct to Cys145. An asparagine hinge (Asn137) couples the helix-turn-helix DNA binding and active site motifs. An arginine finger (Arg128) stabilizes the extrahelical DNA conformation. With this newly improved structural understanding of AGT and its interactions with biologically relevant substrates, we can now begin to unravel the role it plays in preserving genetic integrity and discover how it promotes resistance to anticancer therapies.

Original languageEnglish (US)
Pages (from-to)1100-1115
Number of pages16
JournalDNA Repair
Volume6
Issue number8
DOIs
StatePublished - Aug 1 2007

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Helix-Turn-Helix Motifs
Chemotherapy
Repair
Nucleotides
Drug Therapy
DNA
Catalytic Domain
Neoplasms
Nucleic Acid Conformation
Substrates
Asparagine
Guanine
Fingers
Cysteine
Arginine
Zinc
Hinges
Binding Sites
Ions
Conformations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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DNA binding, nucleotide flipping, and the helix-turn-helix motif in base repair by O6-alkylguanine-DNA alkyltransferase and its implications for cancer chemotherapy. / Tubbs, Julie L.; Pegg, Anthony; Tainer, John A.

In: DNA Repair, Vol. 6, No. 8, 01.08.2007, p. 1100-1115.

Research output: Contribution to journalArticle

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