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    Cryo-EM structure of Pol κ-DNA-PCNA holoenzyme and implications for polymerase switching in DNA lesion bypass

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    Type
    Preprint
    Authors
    Lancey, Claudia cc
    Tehseen, Muhammad cc
    Takahashi, Masateru cc
    Sobhy, Mohamed Abdelmaboud
    Ragan, Timothy J. cc
    Crehuet, Ramon cc
    Hamdan, Samir cc
    De Biasio, Alfredo cc
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Laboratory of DNA Replication and Recombination
    Date
    2020-07-11
    Permanent link to this record
    http://hdl.handle.net/10754/664430
    
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    Abstract
    Replacement of the stalled replicative polymerase (Pol δ) at a DNA lesion by the error-prone DNA polymerase κ (Pol κ) restarts synthesis past the lesion to prevent genome instability. The switching from Pol δ to Pol κ is mediated by the processivity clamp PCNA but the structural basis of this mechanism is unknown. We determined the Cryo-EM structures of human Pol κ-DNA-PCNA complex and of a stalled Pol δ-DNA-PCNA complex at 3.9 and 4.7 Å resolution, respectively. In Pol κ complex, the C-terminus of the PAD domain docks the catalytic core to one PCNA protomer in an angled orientation, bending the DNA exiting Pol κ active site through PCNA. In Pol δ complex, the DNA is disengaged from the active site but is retained by the thumb domain. We present a model for polymerase switching facilitated by Pol κ recruitment to PCNA and Pol κ conformational sampling to seize the DNA from stalled Pol δ assisted by PCNA tilting.
    Citation
    Lancey, C., Tehseen, M., Takahashi, M., Sobhy, M. A., Ragan, T. J., Crehuet, R., … De Biasio, A. (2020). Cryo-EM structure of Pol κ-DNA-PCNA holoenzyme and implications for polymerase switching in DNA lesion bypass. doi:10.1101/2020.07.10.196956
    Sponsors
    This research was supported by King Abdullah University of Science and Technology through core funding (to S.M.H.), and by the Wellcome Trust (to A.D.B.). R.C. acknowledges funding from the MINECO (CTQ2016-78636-P) and to AGAUR, (2017 SGR 324). The MD project has been carried out using CSUC resources. We acknowledge The Midlands Regional Cryo-EM Facility at the Leicester Institute of Structural and Chemical Biology (LISCB), major funding from MRC (MC_PC_17136). We thank Christos Savva (LISCB, University of Leicester) for his help in Cryo-EM data collection and advice on data processing.
    Publisher
    Cold Spring Harbor Laboratory
    DOI
    10.1101/2020.07.10.196956
    Additional Links
    http://biorxiv.org/lookup/doi/10.1101/2020.07.10.196956
    https://www.biorxiv.org/content/biorxiv/early/2020/07/10/2020.07.10.196956.full.pdf
    ae974a485f413a2113503eed53cd6c53
    10.1101/2020.07.10.196956
    Scopus Count
    Collections
    Biological and Environmental Science and Engineering (BESE) Division; Preprints; Bioscience Program

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