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Crystal structure of the human Polϵ B-subunit in complex with the C-terminal domain of the catalytic subunit.

Baranovskiy AG, Gu J, Babayeva ND, Kurinov I, Pavlov YI, Tahirov TH
J Biol Chem 292 15717-15730 (2017)
Cited: 24 times
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Abstract

The eukaryotic B-family DNA polymerases include four members: Polα, Polδ, Polϵ, and Polζ, which share common architectural features, such as the exonuclease/polymerase and C-terminal domains (CTDs) of catalytic subunits bound to indispensable B-subunits, which serve as scaffolds that mediate interactions with other components of the replication machinery. Crystal structures for the B-subunits of Polα and Polδ/Polζ have been reported: the former within the primosome and separately with CTD and the latter with the N-terminal domain of the C-subunit. Here we present the crystal structure of the human Polϵ B-subunit (p59) in complex with CTD of the catalytic subunit (p261C). The structure revealed a well defined electron density for p261C and the phosphodiesterase and oligonucleotide/oligosaccharide-binding domains of p59. However, electron density was missing for the p59 N-terminal domain and for the linker connecting it to the phosphodiesterase domain. Similar to Polα, p261C of Polϵ contains a three-helix bundle in the middle and zinc-binding modules on each side. Intersubunit interactions involving 11 hydrogen bonds and numerous hydrophobic contacts account for stable complex formation with a buried surface area of 3094 Å2 Comparative structural analysis of p59-p261C with the corresponding Polα complex revealed significant differences between the B-subunits and CTDs, as well as their interaction interfaces. The B-subunit of Polδ/Polζ also substantially differs from B-subunits of either Polα or Polϵ. This work provides a structural basis to explain biochemical and genetic data on the importance of B-subunit integrity in replisome function in vivo.

Reviews - 5vbn mentioned but not cited (1)

  1. Diversity and evolution of B-family DNA polymerases. Kazlauskas D, Krupovic M, Guglielmini J, Forterre P, Venclovas Č. Nucleic Acids Res 48 10142-10156 (2020)

Articles - 5vbn mentioned but not cited (9)

  1. Structure of DNA-CMG-Pol epsilon elucidates the roles of the non-catalytic polymerase modules in the eukaryotic replisome. Goswami P, Abid Ali F, Douglas ME, Locke J, Purkiss A, Janska A, Eickhoff P, Early A, Nans A, Cheung AMC, Diffley JFX, Costa A. Nat Commun 9 5061 (2018)
  2. Structure of a human replisome shows the organisation and interactions of a DNA replication machine. Jones ML, Baris Y, Taylor MRG, Yeeles JTP. EMBO J 40 e108819 (2021)
  3. Structure of the DP1-DP2 PolD complex bound with DNA and its implications for the evolutionary history of DNA and RNA polymerases. Raia P, Carroni M, Henry E, Pehau-Arnaudet G, Brûlé S, Béguin P, Henneke G, Lindahl E, Delarue M, Sauguet L. PLoS Biol 17 e3000122 (2019)
  4. Crystal structure of the human Polϵ B-subunit in complex with the C-terminal domain of the catalytic subunit. Baranovskiy AG, Gu J, Gu J, Babayeva ND, Kurinov I, Pavlov YI, Tahirov TH. J Biol Chem 292 15717-15730 (2017)
  5. Iron-Sulfur Clusters in DNA Polymerases and Primases of Eukaryotes. Baranovskiy AG, Siebler HM, Pavlov YI, Tahirov TH. Methods Enzymol 599 1-20 (2018)
  6. HPLC, FTIR and GC-MS Analyses of Thymus vulgaris Phytochemicals Executing In Vitro and In Vivo Biological Activities and Effects on COX-1, COX-2 and Gastric Cancer Genes Computationally. Saleem A, Afzal M, Naveed M, Makhdoom SI, Mazhar M, Aziz T, Khan AA, Kamal Z, Shahzad M, Alharbi M, Alshammari A. Molecules 27 8512 (2022)
  7. Two conformations of DNA polymerase D-PCNA-DNA, an archaeal replisome complex, revealed by cryo-electron microscopy. Mayanagi K, Oki K, Miyazaki N, Ishino S, Yamagami T, Morikawa K, Iwasaki K, Kohda D, Shirai T, Ishino Y. BMC Biol 18 152 (2020)
  8. The physical origin of rate promoting vibrations in enzymes revealed by structural rigidity. Chalopin Y. Sci Rep 10 17465 (2020)
  9. Delineating Pixantrone Maleate's adroit activity against cervical cancer proteins through multitargeted docking-based MM\GBSA, QM-DFT and MD simulation. Almasoudi HH, Nahari MH, Alhazmi AYM, Almasabi SHA, Al-Mansour FSH, Hakami MA. PLoS One 18 e0295714 (2023)


Reviews citing this publication (1)

  1. Structure and function relationships in mammalian DNA polymerases. Hoitsma NM, Whitaker AM, Schaich MA, Smith MR, Fairlamb MS, Freudenthal BD. Cell Mol Life Sci 77 35-59 (2020)

Articles citing this publication (13)

  1. Structure of the processive human Pol δ holoenzyme. Lancey C, Tehseen M, Raducanu VS, Rashid F, Merino N, Ragan TJ, Savva CG, Zaher MS, Shirbini A, Blanco FJ, Hamdan SM, De Biasio A. Nat Commun 11 1109 (2020)
  2. Structure of the polymerase ε holoenzyme and atomic model of the leading strand replisome. Yuan Z, Georgescu R, Schauer GD, O'Donnell ME, Li H. Nat Commun 11 3156 (2020)
  3. Structure and mechanism of B-family DNA polymerase ζ specialized for translesion DNA synthesis. Malik R, Kopylov M, Gomez-Llorente Y, Jain R, Johnson RE, Prakash L, Prakash S, Ubarretxena-Belandia I, Aggarwal AK. Nat Struct Mol Biol 27 913-924 (2020)
  4. Cryo-EM structure and dynamics of eukaryotic DNA polymerase δ holoenzyme. Jain R, Rice WJ, Malik R, Johnson RE, Prakash L, Prakash S, Ubarretxena-Belandia I, Aggarwal AK. Nat Struct Mol Biol 26 955-962 (2019)
  5. Structural evidence for an essential Fe-S cluster in the catalytic core domain of DNA polymerase ϵ. Ter Beek J, Parkash V, Bylund GO, Osterman P, Sauer-Eriksson AE, Johansson E. Nucleic Acids Res 47 5712-5722 (2019)
  6. Activity and fidelity of human DNA polymerase α depend on primer structure. Baranovskiy AG, Duong VN, Babayeva ND, Zhang Y, Pavlov YI, Anderson KS, Tahirov TH. J Biol Chem 293 6824-6843 (2018)
  7. Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that Can Be Exploited by Targeting DNA Polymerase ε. Sviderskiy VO, Blumenberg L, Gorodetsky E, Karakousi TR, Hirsh N, Alvarez SW, Terzi EM, Kaparos E, Whiten GC, Ssebyala S, Tonzi P, Mir H, Neel BG, Huang TT, Adams S, Ruggles KV, Possemato R. Mol Cell 80 682-698.e7 (2020)
  8. A comprehensive mechanistic model of iron metabolism in Saccharomyces cerevisiae. Lindahl PA. Metallomics 11 1779-1799 (2019)
  9. The non-catalytic role of DNA polymerase epsilon in replication initiation in human cells. Vipat S, Gupta D, Jonchhe S, Anderspuk H, Rothenberg E, Moiseeva TN. Nat Commun 13 7099 (2022)
  10. DNA polymerase epsilon binds histone H3.1-H4 and recruits MORC1 to mediate meiotic heterochromatin condensation. Wang C, Huang J, Li Y, Zhang J, He C, Li T, Jiang D, Dong A, Ma H, Copenhaver GP, Wang Y. Proc Natl Acad Sci U S A 119 e2213540119 (2022)
  11. DNA polymerase D temporarily connects primase to the CMG-like helicase before interacting with proliferating cell nuclear antigen. Oki K, Yamagami T, Nagata M, Mayanagi K, Shirai T, Adachi N, Numata T, Ishino S, Ishino Y. Nucleic Acids Res 49 4599-4612 (2021)
  12. The iron-sulfur cluster is essential for DNA binding by human DNA polymerase ε. Lisova AE, Baranovskiy AG, Morstadt LM, Babayeva ND, Stepchenkova EI, Tahirov TH. Sci Rep 12 17436 (2022)
  13. Multiple roles of Pol epsilon in eukaryotic chromosome replication. Cvetkovic MA, Ortega E, Bellelli R, Costa A. Biochem Soc Trans 50 309-320 (2022)


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