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Molecular architecture of the Ub-PCNA/Pol η complex bound to DNA.

<div class='caption-title'>Map validation, overall structure of the 3D reconstruction and atomic model docking.</div>
<div class='caption-title'>Localization of the DNA and its interaction with the complex.</div>
<div class='caption-title'>Structure of the native Ub-PCNA exhibits a conformation different from that of the Ub-PCNA bound to Pol η and DNA.</div>
Lau WC, Li Y, Zhang Q, Huen MS
OpenAccess logo Sci Rep 5 15759 (2015)
Cited: 18 times
EuropePMC logo PMID: 26503230

Abstract

Translesion synthesis (TLS) is the mechanism by which DNA polymerases replicate through unrepaired DNA lesions. TLS is activated by monoubiquitination of the homotrimeric proliferating cell nuclear antigen (PCNA) at lysine-164, followed by the switch from replicative to specialized polymerases at DNA damage sites. Pol η belongs to the Y-Family of specialized polymerases that can efficiently bypass UV-induced lesions. Like other members of the Y-Family polymerases, its recruitment to the damaged sites is mediated by the interaction with monoubiquitinated PCNA (Ub-PCNA) via its ubiquitin-binding domain and non-canonical PCNA-interacting motif in the C-terminal region. The structural determinants underlying the direct recognition of Ub-PCNA by Pol η, or Y-Family polymerases in general, remain largely unknown. Here we report a structure of the Ub-PCNA/Pol η complex bound to DNA determined by single-particle electron microscopy (EM). The overall obtained structure resembles that of the editing PCNA/PolB complex. Analysis of the map revealed the conformation of ubiquitin that binds the C-terminal domain of Pol η. Our present study suggests that the Ub-PCNA/Pol η interaction requires the formation of a structured binding interface, which is dictated by the inherent flexibility of Ub-PCNA.

Reviews - 3ja9 mentioned but not cited (1)

  1. DNA replication: Mechanisms and therapeutic interventions for diseases. Song HY, Shen R, Mahasin H, Guo YN, Wang DG. MedComm (2020) 4 e210 (2023)

Articles - 3ja9 mentioned but not cited (3)

  1. Molecular architecture of the Ub-PCNA/Pol η complex bound to DNA. Lau WC, Li Y, Zhang Q, Huen MS. Sci Rep 5 15759 (2015)
  2. p15PAF binding to PCNA modulates the DNA sliding surface. De March M, Barrera-Vilarmau S, Crespan E, Mentegari E, Merino N, Gonzalez-Magaña A, Romano-Moreno M, Maga G, Crehuet R, Onesti S, Blanco FJ, De Biasio A. Nucleic Acids Res. 46 9816-9828 (2018)
  3. The Rad9-Rad1-Hus1 DNA Repair Clamp is Found in Microsporidia. Mascarenhas Dos Santos AC, Julian AT, Pombert JF. Genome Biol Evol 14 evac053 (2022)


Reviews citing this publication (6)

  1. Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork. Choe KN, Moldovan GL. Mol. Cell 65 380-392 (2017)
  2. Translesion Synthesis: Insights into the Selection and Switching of DNA Polymerases. Zhao L, Washington MT. Genes (Basel) 8 (2017)
  3. Maneuvers on PCNA Rings during DNA Replication and Repair. Slade D. Genes (Basel) 9 (2018)
  4. A defined role for multiple Fanconi anemia gene products in DNA-damage-associated ubiquitination. Tan W, Deans AJ. Exp. Hematol. 50 27-32 (2017)
  5. Fast friends - Ubiquitin-like modifiers as engineered fusion partners. Asimaki E, Petriukov K, Renz C, Meister C, Ulrich HD. Semin Cell Dev Biol 132 132-145 (2022)
  6. Structural basis for the molecular interactions in DNA damage tolerances. Hashimoto H, Hishiki A, Hara K, Kikuchi S. Biophys Physicobiol 14 199-205 (2017)

Articles citing this publication (8)

  1. The C-terminal region of translesion synthesis DNA polymerase η is partially unstructured and has high conformational flexibility. Powers KT, Elcock AH, Washington MT. Nucleic Acids Res. 46 2107-2120 (2018)
  2. Oxaliplatin promotes siMAD2L2‑induced apoptosis in colon cancer cells. Ma L, Li X, Zhao X, Sun H, Kong F, Li Y, Sui Y, Xu F. Mol Med Rep 24 629 (2021)
  3. Preparation and purification of mono-ubiquitinated proteins using Avi-tagged ubiquitin. Tan W, Murphy VJ, Charron A, van Twest S, Sharp M, Constantinou A, Parker MW, Crismani W, Bythell-Douglas R, Deans AJ. PLoS One 15 e0229000 (2020)
  4. Site-specific monoubiquitination downregulates Rab5 by disrupting effector binding and guanine nucleotide conversion. Shin D, Na W, Lee JH, Kim G, Baek J, Park SH, Choi CY, Lee S. Elife 6 (2017)
  5. Photo-activatable Ub-PCNA probes reveal new structural features of the Saccharomyces cerevisiae Polη/PCNA complex. Shen S, Davidson GA, Yang K, Zhuang Z. Nucleic Acids Res 49 9374-9388 (2021)
  6. Small-molecules that bind to the ubiquitin-binding motif of REV1 inhibit REV1 interaction with K164-monoubiquitinated PCNA and suppress DNA damage tolerance. Vanarotti M, Evison BJ, Actis ML, Inoue A, McDonald ET, Shao Y, Heath RJ, Fujii N. Bioorg. Med. Chem. 26 2345-2353 (2018)
  7. Cryo-EM structure of human Pol κ bound to DNA and mono-ubiquitylated PCNA. Lancey C, Tehseen M, Bakshi S, Percival M, Takahashi M, Sobhy MA, Raducanu VS, Blair K, Muskett FW, Ragan TJ, Crehuet R, Hamdan SM, De Biasio A. Nat Commun 12 6095 (2021)
  8. Lsm12 Mediates Deubiquitination of DNA Polymerase η To Help Saccharomyces cerevisiae Resist Oxidative Stress. Yao R, Shi L, Wu C, Qiao W, Liu L, Wu J. Appl. Environ. Microbiol. 85 (2019)


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