The spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase β

Koag, Myong Chul; Nam, Kwangho; Lee, Seongmin

doi:10.1093/nar/gku789

Cited by 56 publications

(96 citation statements)

References 36 publications

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“…There is also evidence that both tautomeric 6–13 (Fig. 1b) and anionic 7–9,14,15 (Fig. 1c) WC-like mismatches can evade such fidelity checkpoints and give rise to replication 6,7 and translation errors 16 .…”

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confidence: 96%

“…1). Protons are generally invisible to X-ray crystallography and cryo-EM 12 , and consequently it has not been possible to unambiguously resolve the identity of WC-like mismatches captured within active sites of polymerases 6,7,15,23 and the ribosome decoding site 9,24 . Moreover, WC-like mismatches are predicted to exist in rapid tautomeric (G enol •T/U⇌G•T enol /U enol ) 25,26 equilibria (Fig.…”

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confidence: 99%

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Dynamic basis for dG•dT misincorporation via tautomerization and ionization

Kimsey

Szymanski

Zahurancik

et al. 2018

Nature

132

183

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Tautomeric and anionic Watson-Crick-like mismatches play important roles in replication and translation errors through mechanisms that are not fully understood. Using NMR relaxation dispersion, we resolved a sequence-dependent kinetic network connecting G•T/U wobbles with three distinct Watson-Crick mismatches consisting of two rapidly exchanging tautomeric species (Genol•T/U⇌G•Tenol/Uenol; population <0.4%) and one anionic species (G•T−/U−; population ≈0.001% at neutral pH). Inserting the sequence-dependent tautomerization/ionization step into a minimal kinetic mechanism for correct incorporation during replication following initial nucleotide binding leads to accurate predictions of dG•dT misincorporation probability across different polymerases, pH conditions, and for a chemically modified nucleotide, and provides mechanisms for sequence-dependent misincorporation. Our results indicate that the energetic penalty for tautomerization/ionization accounts for ≈10−2−10−3–fold discrimination against misincorporation, which proceeds primarily via tautomeric dGenol•dT and dG•dTenol with contributions from anionic dG•dT− dominating at pH ≥8.4 or for some mutagenic nucleotides.

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confidence: 96%

mentioning

confidence: 99%

Dynamic basis for dG•dT misincorporation via tautomerization and ionization

Kimsey

Szymanski

Zahurancik

et al. 2018

Nature

132

183

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“…In this way, in particular, the nature of the so-called error catastrophe[89] can be explained.Further, since endogenous water is not directly included in the processes of the mutagenic tautomerisation that underlie the occurrence of the spontaneous transitionsincorporation errors, so the dependency of the frequency of the latters on pH can be explained by the immediate influence of this physico-chemical factor per se on the course of the G·Т(w)→G*·Т(WC) tautomerisation reaction, that is controlled by not only by the ionization of the isolated bases, incorporated into these pairs[90].…”

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confidence: 99%

How many tautomerization pathways connect Watson–Crick-like G*·T DNA base mispair and wobble mismatches?

Brovarets’

Hovorun

2015

Journal of Biomolecular Structure and Dynamics

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In this study, we have theoretically demonstrated the intrinsic ability of the wobble G·T(w)/G*·T*(w)/G·T(w1)/G·T(w2) and Watson-Crick-like G*·T(WC) DNA base mispairs to interconvert into each other via the DPT tautomerization. We have established that among all these transitions, only one single G·T(w) ↔ G*·T(WC) pathway is eligible from a biological perspective. It involves short-lived intermediate - the G·T*(WC) base mispair - and is governed by the planar, highly stable, and zwitterionic [Formula: see text] transition state stabilized by the participation of the unique pattern of the five intermolecular O6(+)H⋯O4(-), O6(+)H⋯N3(-), N1(+)H⋯N3(-), N1(+)H⋯O2(-), and N2(+)H⋯O2(-) H-bonds. This non-dissociative G·T(w) ↔ G*·T(WC) tautomerization occurs without opening of the pair: Bases within mispair remain connected by 14 different patterns of the specific intermolecular interactions that successively change each other along the IRC. Novel kinetically controlled mechanism of the thermodynamically non-equilibrium spontaneous point GT/TG incorporation errors has been suggested. The mutagenic effect of the analogues of the nucleotide bases, in particular 5-bromouracil, can be attributed to the decreasing of the barrier of the acquisition by the wobble pair containing these compounds of the enzymatically competent Watson-Crick's geometry via the intrapair mutagenic tautomerization directly in the essentially hydrophobic recognition pocket of the replication DNA-polymerase machinery. Proposed approaches are able to explain experimental data, namely growth of the rate of the spontaneous point incorporation errors during DNA biosynthesis with increasing temperature.

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“…Other DNA polymerases such as bacteriophage pol RB69 and human pol ␤ achieve good octahedral coordination geometry not only with Mg 2ϩ but also with Mn 2ϩ at the A-site, as observed in their ternary complex structures with the correct incoming non-hydrolyzable nucleotide (PDB IDs 3SJJ, 3SPY, 2FMS, and 3C2K) (35,41,42). It is notable that the superior coordinating ability of Mn 2ϩ when compared with Mg 2ϩ at the A-site is observed in the previously reported structures of ternary pol ␤ complexes (PDB IDs 4PGQ, 4PGX, 4PHA, and 4PHD) with an incoming incorrect non-hydrolyzable nucleotide (43). Our data and that of others suggest that Mn 2ϩ is more tolerant of atypical pol active sites (e.g.…”

Section: Discussionmentioning

confidence: 63%

Kinetic and Structural Impact of Metal Ions and Genetic Variations on Human DNA Polymerase ι

Choi

Patra

Yeom

et al. 2016

Journal of Biological Chemistry

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with lower values in average coordination distance geometry in the catalytic metal A-site. Crystal structures of R96G revealed the loss of three H-bonds of residues Gly-96 and Tyr-93 with an incoming dNTP, due to the lack of an arginine, as well as a destabilized Tyr-93 side chain secondary to the loss of a cationinteraction between both side chains. These results provide a mechanistic basis for alteration in pol catalytic function with coordinating metals and genetic variation.Genomic DNA is continuously attacked by a variety of endogenous and exogenous agents in cells, and the persistent unrepaired lesions can lead to genomic mutations and related diseases such as cancer. DNA polymerases (pols), 2 as well as DNA repair enzymes, are key enzymes for maintaining or altering genomic integrity against DNA lesions during various DNA transactions in organisms. The DNA replicative mechanisms linked to DNA damage and repair are believed to contribute to producing various mutational signatures in human cancer genomes (1). At least 17 different human DNA polymerases have been identified to date, which differ in their functions in DNA replication, repair, recombination, and damage tolerance (2, 3).Y-family DNA polymerases, including pols , , , and REV1, are specialized in replicating through DNA lesions, so-called translesion DNA synthesis (TLS). These polymerases have low fidelity with undamaged DNA templates but have spacious and solvent-accessible active sites to allow the accommodation and replicative bypass of bulky and distorted DNA lesions (4). Individual Y-family polymerases play error-free or error-prone roles in TLS, depending on DNA lesion types in cells (5). At bulky carcinogen-derived N 2 -G DNA lesions (e.g. benzo[a]pyrene-diol epoxide-G), both pol and REV1 catalyze error-free TLS, but both pols and catalyze error-prone TLS (6 -14). By contrast, at UV-induced cyclobutane thymine dimers (T-T), only pol (but not the other Y-family pols) can catalyze errorfree TLS (15,16). Therefore, the overall balance toward errorfree TLS with all working polymerases at various DNA lesions might be crucial in preventing mutations from numerous genotoxic agents. Recently, we reported that catalytic (either hypoactive or hyperactive) alterations are found in a considerable number of human germline non-synonymous variants of Y-family pols , , and REV1 (17-19), which might potentially influence on the overall TLS capacity in the affected individuals.pol is exceptionally error-prone in DNA synthesis among polymerases, particularly opposite template bases G and T, due to its uniquely restricted active-site and related non-WatsonCrick base pairing (20 -22). pol is able to catalyze nucleotide insertion opposite a variety of DNA lesions, including N 2 -and O 6 -alkyl and aralkyl G adducts, 8-oxo-7,8-dihydroG (8-oxoG),

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The spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase β

Cited by 56 publications

References 36 publications

Dynamic basis for dG•dT misincorporation via tautomerization and ionization

Dynamic basis for dG•dT misincorporation via tautomerization and ionization

How many tautomerization pathways connect Watson–Crick-like G*·T DNA base mispair and wobble mismatches?

Kinetic and Structural Impact of Metal Ions and Genetic Variations on Human DNA Polymerase ι

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