Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA

Banerjee, Anirban; Yang, Wei; Karplus, Martin; Verdine, Gregory L.

doi:10.1038/nature03458

Cited by 346DNA Repair MechanismsEnzyme Structure and FunctionDNA and Nucleic Acid Chemistry

Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA

Banerjee, Anirban, Yang, Wei, Karplus, Martin, Verdine, Gregory L.·2005·Nature

DOI 10.1038/nature03458

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Abstract

How DNA repair proteins distinguish between the rare sites of damage and the vast expanse of normal DNA is poorly understood. Recognizing the mutagenic lesion 8-oxoguanine (oxoG) represents an especially formidable challenge, because this oxidized nucleobase differs by only two atoms from its normal counterpart, guanine (G). Here we report the use of a covalent trapping strategy to capture a human oxoG repair protein, 8-oxoguanine DNA glycosylase I (hOGG1), in the act of interrogating normal DNA. The X-ray structure of the trapped complex features a target G nucleobase extruded from the DNA helix but denied insertion into the lesion recognition pocket of the enzyme. Free energy difference calculations show that both attractive and repulsive interactions have an important role in the preferential binding of oxoG compared with G to the active site. The structure reveals a remarkably effective gate-keeping strategy for lesion discrimination and suggests a mechanism for oxoG insertion into the hOGG1 active site.

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Structures of DNA in complex with OGG1 exist in a catalytically active form for 8oxoG that is adjacent to guanine only in the 5'-position in -AGGT- sequences.
“In fact, the structures of DNA in complex with N-glycosylase/DNA lyase (OGG1), which is a base-excision repair enzyme for 8oxoG, exist in a catalytically active form for 8oxoG that is adjacent to guanine only in the 5’-position in -AGGT- sequences (S12 Fig) [40,48–51].”
From Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling (2018) · cites this paper as [50]

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“In contrast to the ‘‘push–pull’’ mechanism once proposed for nucleotide flipping (2, 5), we observe a two-step process that promotes a kinetic, rather than a thermodynamic (3, 7, 8), gate-keeping strategy for lesion discrimination.”
Background
Lead (Pb) induced Oxidative Stress as a Mechanism to Cause Neurotoxicity in Drosophila melanogaster
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Structural characterization of human 8-oxoguanine DNA glycosylase variants bearing active site mutations
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Duplex interrogation by a direct DNA repair protein in search of base damage
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Reading the chromatinized genome
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OGG1-DNA interactions facilitate NF-κB binding to DNA targets
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8-Oxoguanine incorporation into DNA repeats in vitro and mismatch recognition by MutS
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“OGG1 scans the helix and, possible alerted to the presence of its substrate by an altered torsional rigidity in the DNA (48,49), extrudes the oxidized base from the helix and accommodates it deep within the active site (50,51).”
Background
hOGG1 Ser326Cys polymorphism and susceptibility to gallbladder cancer in a Chinese population
Jiao, X., Huang, J., Wu, S., MingdeLv, Hu, Y., Jianfu, Su, X., Luo, C., & Broelsch, C. (2007) · International Journal of Cancer · doi:10.1002/ijc.22748 · Cited by 72 · see citing works
“Thus, organisms have developed a highly efficient DNA repair machinery consisting of several genes and pathways responsible for removing and repairing damaged DNA; interindividual variation in the repair capacity have been implicated as a cancer susceptibility factor.(21)”
Background
Isolation, Characterization, and Independent Synthesis of Guanine Oxidation Products
Gimisis, T., & Cismaş, C. (2006) · European Journal of Organic Chemistry · doi:10.1002/ejoc.200500581 · Cited by 71 · see citing works
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Kinetic Conformational Analysis of Human 8-Oxoguanine-DNA Glycosylase
Kuznetsov, N. A., Koval, V. V., Nevinsky, G. A., Douglas, K. T., Zharkov, D. O., & Fedorova, O. S. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605788200 · Cited by 69 · see citing works
Extrahelical Damaged Base Recognition by DNA Glycosylase Enzymes
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Increased 8-hydroxy-2′-deoxyguanosine in plasma and decreased mRNA expression of human 8-oxoguanine DNA glycosylase 1, anti-oxidant enzymes, mitochondrial biogenesis-related proteins and glycolytic enzymes in leucocytes in patients with systemic lupus erythematosus
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UVA irradiation induces relocalisation of the DNA repair protein hOGG1 to nuclear speckles
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“One open question is how hOGG1 and other proteins initiating DNA repair manage to find and repair the damaged DNA, especially considering the high degree of DNA condensation in the cell nucleus (Halford and Marko, 2004; Banerjee et al., 2005).”
Background
Efficient Removal of Formamidopyrimidines by 8-Oxoguanine Glycosylases
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Background
Uracil-Directed Ligand Tethering: An Efficient Strategy for Uracil DNA Glycosylase (UNG) Inhibitor Development
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Background
Tautomerization-dependent recognition and excision of oxidation damage in base-excision DNA repair
Zhu, C., Lu, L., Zhang, J., Yue, Z., Song, J., Zong, S., Liu, M., Stovicek, O., Gao, Y. Q., & Yi, C. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604591113 · Cited by 64 · see citing works
“The use of different binding pockets to discriminate a flipped base has precedence in the case of hOGG1, which uses two distinct pockets for recognizing oxoG and G (43).”
Background
Studying protein-DNA interactions using atomic force microscopy
Beckwitt, E. C., Kong, M., & Houten, B. V. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.06.028 · Cited by 64 · see citing works
“sapiens Nonspecific 0, 33, 70 1 9, 9, 9 [55] Nonspecific 80 1YQK [116] 2”
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Facilitated Diffusion Mechanisms in DNA Base Excision Repair and Transcriptional Activation
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Synthesis and Structure of Duplex DNA Containing the Genotoxic Nucleobase Lesion N7-Methylguanine
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Lesion processing by a repair enzyme is severely curtailed by residues needed to prevent aberrant activity on undamaged DNA
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Synthesis of Site-Specific DNA–Protein Conjugates and Their Effects on DNA Replication
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Twist-open mechanism of DNA damage recognition by the Rad4/XPC nucleotide excision repair complex
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Alzheimer's disease-associated polymorphisms in human OGG1 alter catalytic activity and sensitize cells to DNA damage
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Damage Detection and Base Flipping in Direct DNA Alkylation Repair
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CUX2 Protein Functions as an Accessory Factor in the Repair of Oxidative DNA Damage
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8-Oxoguanine DNA Glycosylases: One Lesion, Three Subfamilies
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“the steric hindrance created by the alanine methyl group [40].”
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Correct and incorrect nucleotide incorporation pathways in DNA polymerase β
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Intermittent Fluorescence Oscillations in Lipid Droplets in a Live Normal and Lung Cancer Cell: Time-Resolved Confocal Microscopy
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Enforced Presentation of an Extrahelical Guanine to the Lesion Recognition Pocket of Human 8-Oxoguanine Glycosylase, hOGG1
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“We were quite intrigued by this seemingly perfect superposition between the dDXL G-complex and the LRC, given the significant calculated energy difference between inserting a G versus an oxoG into the active site (34).”
BackgroundMethodInfluential
Active destabilization of base pairs by a DNA glycosylase wedge initiates damage recognition
Kuznetsov, N. A., Bergonzo, C., Campbell, A. J., Li, H., Mechetin, G. V., Santos, C. D. L., Grollman, A. P., Fedorova, O. S., Zharkov, D. O., & Simmerling, C. L. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1300 · Cited by 54 · see citing works
“Structural studies with three other DNA glycosylases, human 8-oxoguanine-DNA glycosylase OGG1 (34,35), human uracil-DNA glycosylase (36) and E. coli alkylpurine-DNA glycosylase AlkA (37) suggest that extensive sampling of normal bases ending in a catalytically improper conformation of the enzyme– substrate complex may…”
Background
Enzymatically inactive OGG1 binds to DNA and steers base excision repair toward gene transcription
Hao, W., Wang, J., Zhang, Y., Wang, C., Xia, L., Zhang, W., Zafar, M., Kang, J., Wang, R., Bohio, A. A., et al. (2020) · The FASEB Journal · doi:10.1096/fj.201902243r · Cited by 51 · see citing works
Synthesis of Sequence-Specific DNA–Protein Conjugates via a Reductive Amination Strategy
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2-Aminopurine Flipped into the Active Site of the Adenine-Specific DNA Methyltransferase M.TaqI: Crystal Structures and Time-Resolved Fluorescence
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Step-by-step mechanism of DNA damage recognition by human 8-oxoguanine DNA glycosylase
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“coli endonuclease III (Nth) [57], 8-oxoguanine DNA glycosylase OGG1 [15,21,35,202] and human alkyl adenine glycosylase (AAG) [93].”
A nucleobase lesion remodels the interaction of its normal neighbor in a DNA glycosylase complex
Banerjee, A., & Verdine, G. L. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603644103 · Cited by 48 · see citing works
Self-citation
Lost in the Crowd: How Does Human 8-Oxoguanine DNA Glycosylase 1 (OGG1) Find 8-Oxoguanine in the Genome?
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Mechanism of DNA loading by the DNA repair helicase XPD
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Catalytic Mechanism of Cellulose Degradation by a Cellobiohydrolase, CelS
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“as implemented in CHARMM. The SCC-DFTB method is a fast semi-empirical density functional approach that has been extensively tested and applied to several enzymes”
Method
hSSB1 (NABP2/ OBFC2B) is required for the repair of 8-oxo-guanine by the hOGG1-mediated base excision repair pathway
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“While the modality of binding to the 8-oxoG is well documented (8,40), the selective recognition of the damaged base versus unmodified guanine is still not well understood.”
Background
Entrapment and Structure of an Extrahelical Guanine Attempting to Enter the Active Site of a Bacterial DNA Glycosylase, MutM
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Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1
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“The covalent tethering of substrates to enzymes has proven to be an effective strategy for capturing difficult to characterize enzyme–substrate complexes, leading to their structural characterization (26, 27).”
Background
Oxidative lesions modulate G-quadruplex stability and structure in the human BCL2 promoter
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“OGG1 initiates excision by hydrogen bonding with the protonated N7 of oxoG (61,62).”
Background

Enforced Presentation of an Extrahelical Guanine to the Lesion Recognition Pocket of Human 8-Oxoguanine Glycosylase, hOGG1
Nartey, C. M., Nam, K., Oo, K., Kutchukian, P. S., Bowman, B. R., Karplus, M., & Verdine, G. L. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.316497 · Cited by 54 · see citing works
The trajectory of intrahelical lesion recognition and extrusion by the human 8-oxoguanine DNA glycosylase
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DNA search and rescue
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Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA
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A nucleobase lesion remodels the interaction of its normal neighbor in a DNA glycosylase complex
Banerjee, A., & Verdine, G. L. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603644103 · Cited by 48 · see citing works
Self-citation

Authors: Banerjee, A., Yang, W., Karplus, M., & Verdine, G. L.
Affiliations: Harvard University (US)
Institut de Science et d'Ingénierie Supramoléculaires (FR)
Corresponding author: Karplus, Martin
Verdine, Gregory L.
ORCID: Banerjee, Anirban
Yang, Wei
Karplus, Martin
Verdine, Gregory L.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2005-03
Volume: 434
Issue: 7033
Pages: 612-618
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature03458
OpenAlex: W2077615862
Cited by: 346
References: 31
Citations by year: 2026: 8 · 2025: 9 · 2024: 8 · 2023: 6 · 2022: 16 · 2021: 16 · 2020: 15 · 2019: 10 · 2018: 19 · 2017: 20 · 2016: 14 · 2015: 18 · 2014: 15 · 2013: 11 · 2012: 18
FWCI: 10.71
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health
National Cancer Institute (R01CA100742)
National Institute of General Medical Sciences (R01GM044853)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords: OGG1, 8-oxoguanine, oxidative DNA damage, DNA repair, lesion recognition, X-ray crystal structure, free energy difference
MeSH terms: Base Sequence, Binding Sites, Computer Simulation, Disulfides, DNA, DNA Damage, DNA Repair, Guanine, Humans, Models, Molecular, Nucleic Acid Conformation, Protein Conformation, Structure-Activity Relationship, Substrate Specificity, Thermodynamics, Reproducibility of Results, Crystallography, X-Ray, DNA Glycosylases

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Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA

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