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Capturing snapshots of APE1 processing DNA damage.

<div class='caption-title'>High-resolution APE1:DNA product complex</div>
<div class='caption-title'>R181 swings to facilitate product stability</div>
<div class='caption-title'>R177 intercalates into the major groove anchoring the orphan base</div>
Freudenthal BD, Beard WA, Cuneo MJ, Dyrkheeva NS, Wilson SH
OpenAccess logo Nat Struct Mol Biol 22 924-31 (2015)
Related entries: 5dff, 5dfi, 5dfj, 5dg0

Cited: 76 times
EuropePMC logo PMID: 26458045

Abstract

DNA apurinic-apyrimidinic (AP) sites are prevalent noncoding threats to genomic stability and are processed by AP endonuclease 1 (APE1). APE1 incises the AP-site phosphodiester backbone, generating a DNA-repair intermediate that is potentially cytotoxic. The molecular events of the incision reaction remain elusive, owing in part to limited structural information. We report multiple high-resolution human APE1-DNA structures that divulge new features of the APE1 reaction, including the metal-binding site, the nucleophile and the arginine clamps that mediate product release. We also report APE1-DNA structures with a T-G mismatch 5' to the AP site, representing a clustered lesion occurring in methylated CpG dinucleotides. These structures reveal that APE1 molds the T-G mismatch into a unique Watson-Crick-like geometry that distorts the active site, thus reducing incision. These snapshots provide mechanistic clarity for APE1 while affording a rational framework to manipulate biological responses to DNA damage.

Articles - 5dfh mentioned but not cited (1)

  1. Capturing snapshots of APE1 processing DNA damage. Freudenthal BD, Beard WA, Cuneo MJ, Dyrkheeva NS, Wilson SH. Nat Struct Mol Biol 22 924-931 (2015)


Reviews citing this publication (11)

  1. Base excision repair of oxidative DNA damage: from mechanism to disease. Whitaker AM, Schaich MA, Smith MR, Flynn TS, Freudenthal BD. Front Biosci (Landmark Ed) 22 1493-1522 (2017)
  2. Eukaryotic Base Excision Repair: New Approaches Shine Light on Mechanism. Beard WA, Horton JK, Prasad R, Wilson SH. Annu Rev Biochem 88 137-162 (2019)
  3. APE1: A skilled nucleic acid surgeon. Whitaker AM, Freudenthal BD. DNA Repair (Amst) 71 93-100 (2018)
  4. The involvement of nucleotide excision repair proteins in the removal of oxidative DNA damage. Kumar N, Raja S, Van Houten B. Nucleic Acids Res 48 11227-11243 (2020)
  5. Functions of the major abasic endonuclease (APE1) in cell viability and genotoxin resistance. McNeill DR, Whitaker AM, Stark WJ, Illuzzi JL, McKinnon PJ, Freudenthal BD, Wilson DM. Mutagenesis 35 27-38 (2020)
  6. Molecular Mechanisms Regulating the DNA Repair Protein APE1: A Focus on Its Flexible N-Terminal Tail Domain. López DJ, Rodríguez JA, Bañuelos S. Int J Mol Sci 22 6308 (2021)
  7. XRCC1 - Strategies for coordinating and assembling a versatile DNA damage response. London RE. DNA Repair (Amst) 93 102917 (2020)
  8. Understanding APE1 cellular functions by the structural preference of exonuclease activities. Liu TC, Guo KW, Chu JW, Hsiao YY. Comput Struct Biotechnol J 19 3682-3691 (2021)
  9. Obstacles and opportunities for base excision repair in chromatin. Biechele-Speziale DJ, Sutton TB, Delaney S. DNA Repair (Amst) 116 103345 (2022)
  10. Not making the cut: Techniques to prevent RNA cleavage in structural studies of RNase-RNA complexes. Jones SP, Goossen C, Lewis SD, Delaney AM, Gleghorn ML. J Struct Biol X 6 100066 (2022)
  11. Nucleophosmin Plays a Role in Repairing DNA Damage and Is a Target for Cancer Treatment. Sekhar KR, Freeman ML. Cancer Res 83 1573-1580 (2023)

Articles citing this publication (64)

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  26. Crystal structure and functional properties of the human CCR4-CAF1 deadenylase complex. Chen Y, Khazina E, Izaurralde E, Weichenrieder O. Nucleic Acids Res 49 6489-6510 (2021)
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  30. Environmental Effects on Guanine-Thymine Mispair Tautomerization Explored with Quantum Mechanical/Molecular Mechanical Free Energy Simulations. Li P, Rangadurai A, Al-Hashimi HM, Hammes-Schiffer S. J Am Chem Soc 142 11183-11191 (2020)
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  33. Thermococcus Eurythermalis Endonuclease IV Can Cleave Various Apurinic/Apyrimidinic Site Analogues in ssDNA and dsDNA. Wang WW, Zhou H, Xie JJ, Yi GS, He JH, Wang FP, Xiao X, Liu XP. Int J Mol Sci 20 E69 (2018)
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  36. Histone H3 Lysine 56 Acetylation Enhances AP Endonuclease 1-Mediated Repair of AP Sites in Nucleosome Core Particles. Rodriguez Y, Horton JK, Wilson SH. Biochemistry 58 3646-3655 (2019)
  37. Mutational and Kinetic Analysis of APE1 Endoribonuclease Activity. Kuznetsova AA, Gavrilova AA, Novopashina DS, Fedorova OS, Kuznetsov NA. Mol Biol 55 211-224 (2021)
  38. Polymorphism of apyrimidinic DNA structures in the nucleosome. Osakabe A, Arimura Y, Matsumoto S, Horikoshi N, Sugasawa K, Kurumizaka H. Sci Rep 7 41783 (2017)
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  41. The Enigma of Substrate Recognition and Catalytic Efficiency of APE1-Like Enzymes. Davletgildeeva AT, Ishchenko AA, Saparbaev M, Fedorova OS, Kuznetsov NA. Front Cell Dev Biol 9 617161 (2021)
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  43. Human TDP1, APE1 and TREX1 repair 3'-DNA-peptide/protein cross-links arising from abasic sites in vitro. Wei X, Wang Z, Hinson C, Yang K. Nucleic Acids Res 50 3638-3657 (2022)
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  46. Comparative Analysis of Exo- and Endonuclease Activities of APE1-like Enzymes. Davletgildeeva AT, Kuznetsova AA, Novopashina DS, Ishchenko AA, Saparbaev M, Fedorova OS, Kuznetsov NA. Int J Mol Sci 23 2869 (2022)
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  60. Functional importance and divergence of plant apurinic/apyrimidinic endonucleases in somatic and meiotic DNA repair. Li J, Wang C, Liang W, Zhang J, Jiang CK, Liu Y, Ren Z, Ci D, Chang J, Han S, Deng XW, Wang Y, Qian W. Plant Cell 35 2316-2331 (2023)
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  63. Structural dissection of sequence recognition and catalytic mechanism of human LINE-1 endonuclease. Miller I, Totrov M, Korotchkina L, Kazyulkin DN, Gudkov AV, Korolev S. Nucleic Acids Res 49 11350-11366 (2021)
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