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Structural basis for the inhibition of human alkyladenine DNA glycosylase (AAG) by 3,N4-ethenocytosine-containing DNA.

Lingaraju GM, Davis CA, Setser JW, Samson LD, Drennan CL
J Biol Chem 286 13205-13 (2011)
Cited: 18 times
EuropePMC logo PMID: 21349833

Abstract

Reactive oxygen and nitrogen species, generated by neutrophils and macrophages in chronically inflamed tissues, readily damage DNA, producing a variety of potentially genotoxic etheno base lesions; such inflammation-related DNA damage is now known to contribute to carcinogenesis. Although the human alkyladenine DNA glycosylase (AAG) can specifically bind DNA containing either 1,N(6)-ethenoadenine (εA) lesions or 3,N(4)-ethenocytosine (εC) lesions, it can only excise εA lesions. AAG binds very tightly to DNA containing εC lesions, forming an abortive protein-DNA complex; such binding not only shields εC from repair by other enzymes but also inhibits AAG from acting on other DNA lesions. To understand the structural basis for inhibition, we have characterized the binding of AAG to DNA containing εC lesions and have solved a crystal structure of AAG bound to a DNA duplex containing the εC lesion. This study provides the first structure of a DNA glycosylase in complex with an inhibitory base lesion that is induced endogenously and that is also induced upon exposure to environmental agents such as vinyl chloride. We identify the primary cause of inhibition as a failure to activate the nucleotide base as an efficient leaving group and demonstrate that the higher binding affinity of AAG for εC versus εA is achieved through formation of an additional hydrogen bond between Asn-169 in the active site pocket and the O(2) of εC. This structure provides the basis for the design of AAG inhibitors currently being sought as an adjuvant for cancer chemotherapy.

Reviews - 3qi5 mentioned but not cited (2)

  1. Recent advances in the structural mechanisms of DNA glycosylases. Brooks SC, Adhikary S, Rubinson EH, Eichman BF. Biochim Biophys Acta 1834 247-271 (2013)
  2. Facilitated Diffusion Mechanisms in DNA Base Excision Repair and Transcriptional Activation. Esadze A, Stivers JT. Chem Rev 118 11298-11323 (2018)

Articles - 3qi5 mentioned but not cited (3)

  1. Structural basis for the inhibition of human alkyladenine DNA glycosylase (AAG) by 3,N4-ethenocytosine-containing DNA. Lingaraju GM, Davis CA, Setser JW, Samson LD, Drennan CL. J Biol Chem 286 13205-13213 (2011)
  2. Searching for DNA lesions: structural evidence for lower- and higher-affinity DNA binding conformations of human alkyladenine DNA glycosylase. Setser JW, Lingaraju GM, Davis CA, Samson LD, Drennan CL. Biochemistry 51 382-390 (2012)
  3. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)


Reviews citing this publication (1)

  1. Regulation of DNA Alkylation Damage Repair: Lessons and Therapeutic Opportunities. Soll JM, Sobol RW, Mosammaparast N. Trends Biochem Sci 42 206-218 (2017)

Articles citing this publication (12)

  1. DNA repair is indispensable for survival after acute inflammation. Calvo JA, Meira LB, Lee CY, Moroski-Erkul CA, Abolhassani N, Taghizadeh K, Eichinger LW, Muthupalani S, Nordstrand LM, Klungland A, Samson LD. J Clin Invest 122 2680-2689 (2012)
  2. Direct repair of 3,N(4)-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase. Fu D, Samson LD. DNA Repair (Amst) 11 46-52 (2012)
  3. Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression. Montaldo NP, Bordin DL, Brambilla A, Rösinger M, Fordyce Martin SL, Bjørås KØ, Bradamante S, Aas PA, Furrer A, Olsen LC, Kunath N, Otterlei M, Sætrom P, Bjørås M, Samson LD, van Loon B. Nat Commun 10 5460 (2019)
  4. RNA ligase-like domain in activating signal cointegrator 1 complex subunit 1 (ASCC1) regulates ASCC complex function during alkylation damage. Soll JM, Brickner JR, Mudge MC, Mosammaparast N. J Biol Chem 293 13524-13533 (2018)
  5. Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation-π interactions. Wilkinson OJ, Latypov V, Tubbs JL, Millington CL, Morita R, Blackburn H, Marriott A, McGown G, Thorncroft M, Watson AJ, Connolly BA, Grasby JA, Masui R, Hunter CA, Tainer JA, Margison GP, Williams DM. Proc Natl Acad Sci U S A 109 18755-18760 (2012)
  6. Modeling the chemical step utilized by human alkyladenine DNA glycosylase: a concerted mechanism AIDS in selectively excising damaged purines. Rutledge LR, Wetmore SD. J Am Chem Soc 133 16258-16269 (2011)
  7. A novel role for transcription-coupled nucleotide excision repair for the in vivo repair of 3,N4-ethenocytosine. Chaim IA, Gardner A, Wu J, Iyama T, Wilson DM, Samson LD. Nucleic Acids Res 45 3242-3252 (2017)
  8. Repair kinetics of acrolein- and (E)-4-hydroxy-2-nonenal-derived DNA adducts in human colon cell extracts. Choudhury S, Dyba M, Pan J, Roy R, Chung FL. Mutat Res 751-752 15-23 (2013)
  9. Defining the functional footprint for recognition and repair of deaminated DNA. Baldwin MR, O'Brien PJ. Nucleic Acids Res 40 11638-11647 (2012)
  10. The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury. Yu AM, Calvo JA, Muthupalani S, Samson LD. Oncotarget 7 28624-28636 (2016)
  11. Search for DNA damage by human alkyladenine DNA glycosylase involves early intercalation by an aromatic residue. Hendershot JM, O'Brien PJ. J Biol Chem 292 16070-16080 (2017)
  12. Recognition of 1,N2-ethenoguanine by alkyladenine DNA glycosylase is restricted by a conserved active-site residue. Thelen AZ, O'Brien PJ. J Biol Chem 295 1685-1693 (2020)


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