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A crystallographic study of the role of sequence context in thymine glycol bypass by a replicative DNA polymerase serendipitously sheds light on the exonuclease complex.

Aller P, Duclos S, Wallace SS, Doublié S
J Mol Biol 412 22-34 (2011)
Related entries: 2dy4, 3rma, 3rmb, 3rmc

Cited: 21 times
EuropePMC logo PMID: 21781974

Abstract

Thymine glycol (Tg) is the most common oxidation product of thymine and is known to be a strong block to replicative DNA polymerases. A previously solved structure of the bacteriophage RB69 DNA polymerase (RB69 gp43) in complex with Tg in the sequence context 5'-G-Tg-G shed light on how Tg blocks primer elongation: The protruding methyl group of the oxidized thymine displaces the adjacent 5'-G, which can no longer serve as a template for primer elongation [Aller, P., Rould, M. A., Hogg, M, Wallace, S. S. & Doublié S. (2007). A structural rationale for stalling of a replicative DNA polymerase at the most common oxidative thymine lesion, thymine glycol. Proc. Natl. Acad. Sci. USA, 104, 814-818.]. Several studies showed that in the sequence context 5'-C-Tg-purine, Tg is more likely to be bypassed by Klenow fragment, an A-family DNA polymerase. We set out to investigate the role of sequence context in Tg bypass in a B-family polymerase and to solve the crystal structures of the bacteriophage RB69 DNA polymerase in complex with Tg-containing DNA in the three remaining sequence contexts: 5'-A-Tg-G, 5'-T-Tg-G, and 5'-C-Tg-G. A combination of several factors-including the associated exonuclease activity, the nature of the 3' and 5' bases surrounding Tg, and the cis-trans interconversion of Tg-influences Tg bypass. We also visualized for the first time the structure of a well-ordered exonuclease complex, allowing us to identify and confirm the role of key residues (Phe123, Met256, and Tyr257) in strand separation and in the stabilization of the primer strand in the exonuclease site.

Articles - 3rmd mentioned but not cited (2)

  1. A crystallographic study of the role of sequence context in thymine glycol bypass by a replicative DNA polymerase serendipitously sheds light on the exonuclease complex. Aller P, Duclos S, Wallace SS, Doublié S. J Mol Biol 412 22-34 (2011)
  2. Mutations conferring resistance to viral DNA polymerase inhibitors in camelpox virus give different drug-susceptibility profiles in vaccinia virus. Duraffour S, Andrei G, Topalis D, Krečmerová M, Crance JM, Garin D, Snoeck R. J Virol 86 7310-7325 (2012)


Reviews citing this publication (3)

  1. DNA polymerase ε and its roles in genome stability. Henninger EE, Pursell ZF. IUBMB Life 66 339-351 (2014)
  2. Structural insights into eukaryotic DNA replication. Doublié S, Zahn KE. Front Microbiol 5 444 (2014)
  3. Utility of the bacteriophage RB69 polymerase gp43 as a surrogate enzyme for herpesvirus orthologs. Bennett N, Götte M. Viruses 5 54-86 (2013)

Articles citing this publication (16)

  1. Structural characterization of viral ortholog of human DNA glycosylase NEIL1 bound to thymine glycol or 5-hydroxyuracil-containing DNA. Imamura K, Averill A, Wallace SS, Doublié S. J Biol Chem 287 4288-4298 (2012)
  2. Mechanisms of base substitution mutagenesis in cancer genomes. Bacolla A, Cooper DN, Vasquez KM. Genes (Basel) 5 108-146 (2014)
  3. Molecular recognition of canonical and deaminated bases by P. abyssi family B DNA polymerase. Gouge J, Ralec C, Henneke G, Delarue M. J Mol Biol 423 315-336 (2012)
  4. The RECQL4 protein, deficient in Rothmund-Thomson syndrome is active on telomeric D-loops containing DNA metabolism blocking lesions. Ferrarelli LK, Popuri V, Ghosh AK, Tadokoro T, Canugovi C, Hsu JK, Croteau DL, Bohr VA. DNA Repair (Amst) 12 518-528 (2013)
  5. DNA polymerase 3'→5' exonuclease activity: Different roles of the beta hairpin structure in family-B DNA polymerases. Darmawan H, Harrison M, Reha-Krantz LJ. DNA Repair (Amst) 29 36-46 (2015)
  6. DNA polymerase hybrids derived from the family-B enzymes of Pyrococcus furiosus and Thermococcus kodakarensis: improving performance in the polymerase chain reaction. Elshawadfy AM, Keith BJ, Ee Ooi H, Kinsman T, Heslop P, Connolly BA. Front Microbiol 5 224 (2014)
  7. Molecular events during translocation and proofreading extracted from 200 static structures of DNA polymerase. Ren Z. Nucleic Acids Res 44 7457-7474 (2016)
  8. Unwinding of primer-templates by archaeal family-B DNA polymerases in response to template-strand uracil. Richardson TT, Wu X, Keith BJ, Heslop P, Jones AC, Connolly BA. Nucleic Acids Res 41 2466-2478 (2013)
  9. Impact of thymine glycol damage on DNA duplex energetics: Correlations with lesion-induced biochemical and structural consequences. Minetti CA, Remeta DP, Iden CR, Johnson F, Grollman AP, Breslauer KJ. Biopolymers 103 491-508 (2015)
  10. Human DNA polymerase β, but not λ, can bypass a 2-deoxyribonolactone lesion together with proliferating cell nuclear antigen. Crespan E, Pasi E, Imoto S, Hübscher U, Greenberg MM, Maga G. ACS Chem Biol 8 336-344 (2013)
  11. In Vitro Bypass of Thymidine Glycol by DNA Polymerase θ Forms Sequence-Dependent Frameshift Mutations. Laverty DJ, Greenberg MM. Biochemistry 56 6726-6733 (2017)
  12. Polymerase and exonuclease activities in herpes simplex virus type 1 DNA polymerase are not highly coordinated. Vashishtha AK, Kuchta RD. Biochemistry 54 240-249 (2015)
  13. Insights into DNA polymerase δ's mechanism for accurate DNA replication. Foley MC, Couto L, Rauf S, Boyke A. J Mol Model 25 80 (2019)
  14. Structure of New Binary and Ternary DNA Polymerase Complexes From Bacteriophage RB69. Park J, Youn HS, An JY, Lee Y, Eom SH, Wang J. Front Mol Biosci 8 704813 (2021)
  15. Dynamics of 5R-Tg Base Flipping in DNA Duplexes Based on Simulations─Agreement with Experiments and Beyond. Wang SD, Eriksson LA, Zhang RB. J Chem Inf Model 62 386-398 (2022)
  16. Tracking of progressing human DNA polymerase δ holoenzymes reveals distributions of DNA lesion bypass activities. Dannenberg RL, Cardina JA, Pytko KG, Hedglin M. Nucleic Acids Res 50 9893-9908 (2022)


Related citations provided by authors (1)

  1. A structural rationale for stalling of a replicative DNA polymerase at the most common oxidative thymine lesion, thymine glycol.. Aller P, Rould MA, Hogg M, Wallace SS, Doublié S Proc Natl Acad Sci U S A 104 814-8 (2007)

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