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A fidelity mechanism in DNA polymerase lambda promotes error-free bypass of 8-oxo-dG.

Burak MJ, Guja KE, Hambardjieva E, Derkunt B, Garcia-Diaz M
EMBO J 35 2045-59 (2016)
Related entries: 5iii, 5iij, 5iik, 5iil, 5iim, 5iin

Cited: 16 times
EuropePMC logo PMID: 27481934

Abstract

8-oxo-7,8-dihydroxy-2'-deoxyguanosine (8-oxo-dG) has high mutagenic potential as it is prone to mispair with deoxyadenine (dA). In order to maintain genomic integrity, post-replicative 8-oxo-dG:dA mispairs are removed through DNA polymerase lambda (Pol λ)-dependent MUTYH-initiated base excision repair (BER). Here, we describe seven novel crystal structures and kinetic data that fully characterize 8-oxo-dG bypass by Pol λ. We demonstrate that Pol λ has a flexible active site that can tolerate 8-oxo-dG in either the anti- or syn-conformation. Importantly, we show that discrimination against the pro-mutagenic syn-conformation occurs at the extension step and identify the residue responsible for this selectivity. This residue acts as a kinetic switch, shunting repair toward long-patch BER upon correct dCMP incorporation, thus enhancing repair efficiency. Moreover, this switch also provides a potential mechanism to increase repair fidelity of MUTYH-initiated BER.

Reviews - 5iio mentioned but not cited (1)

  1. Structural Insights into the Specificity of 8-Oxo-7,8-dihydro-2'-deoxyguanosine Bypass by Family X DNA Polymerases. Kaminski AM, Kunkel TA, Pedersen LC, Bebenek K. Genes (Basel) 13 15 (2021)

Articles - 5iio mentioned but not cited (2)

  1. A fidelity mechanism in DNA polymerase lambda promotes error-free bypass of 8-oxo-dG. Burak MJ, Guja KE, Hambardjieva E, Derkunt B, Garcia-Diaz M. EMBO J. 35 2045-2059 (2016)
  2. Unexpected behavior of DNA polymerase Mu opposite template 8-oxo-7,8-dihydro-2'-guanosine. Kaminski AM, Chiruvella KK, Ramsden DA, Kunkel TA, Bebenek K, Pedersen LC. Nucleic Acids Res. 47 9410-9422 (2019)


Reviews citing this publication (3)

  1. Sunlight damage to cellular DNA: Focus on oxidatively generated lesions. Schuch AP, Moreno NC, Schuch NJ, Menck CFM, Garcia CCM. Free Radic. Biol. Med. 107 110-124 (2017)
  2. DNA polymerase mu: An inflexible scaffold for substrate flexibility. Kaminski AM, Bebenek K, Pedersen LC, Kunkel TA. DNA Repair (Amst) 93 102932 (2020)
  3. Polymerases and DNA Repair in Neurons: Implications in Neuronal Survival and Neurodegenerative Diseases. Li X, Cao G, Liu X, Tang TS, Guo C, Liu H. Front Cell Neurosci 16 852002 (2022)

Articles citing this publication (10)

  1. Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase. Rechkoblit O, Johnson RE, Gupta YK, Prakash L, Prakash S, Aggarwal AK. Nat Commun 12 4020 (2021)
  2. Crystal structures of ternary complexes of archaeal B-family DNA polymerases. Kropp HM, Betz K, Wirth J, Diederichs K, Marx A. PLoS ONE 12 e0188005 (2017)
  3. Single molecule analysis indicates stimulation of MUTYH by UV-DDB through enzyme turnover. Jang S, Schaich MA, Khuu C, Schnable BL, Majumdar C, Watkins SC, David SS, Van Houten B. Nucleic Acids Res 49 8177-8188 (2021)
  4. Dynamic basis for dA•dGTP and dA•d8OGTP misincorporation via Hoogsteen base pairs. Gu S, Szymanski ES, Rangadurai AK, Shi H, Liu B, Manghrani A, Al-Hashimi HM. Nat Chem Biol 19 900-910 (2023)
  5. Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide. Jamsen JA, Sassa A, Shock DD, Beard WA, Wilson SH. Nat Commun 12 2059 (2021)
  6. Watching right and wrong nucleotide insertion captures hidden polymerase fidelity checkpoints. Jamsen JA, Shock DD, Wilson SH. Nat Commun 13 3193 (2022)
  7. Analysis of diverse double-strand break synapsis with Polλ reveals basis for unique substrate specificity in nonhomologous end-joining. Kaminski AM, Chiruvella KK, Ramsden DA, Bebenek K, Kunkel TA, Pedersen LC. Nat Commun 13 3806 (2022)
  8. Estimation of the Mutagenic Potential of 8-Oxog in Nuclear Extracts of Mouse Cells Using the "Framed Mirror" Method. Gening LV, Volodin AA, Kazachenko KY, Makarova IV, Tarantul VZ. Methods Protoc 3 (2020)
  9. On the Role of Molecular Conformation of the 8-Oxoguanine Lesion in Damaged DNA Processing by Polymerases. Geronimo I, Vidossich P, De Vivo M. J Chem Inf Model 63 1521-1528 (2023)
  10. Synthesis of 8-oxo-dGTP and its β,γ-CH2-, β, γ-CHF-, and β, γ-CF2- analogues. Zheng Y, Haratipour P, Kashemirov BA, McKenna CE. Tetrahedron Lett 67 152890 (2021)


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