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Global landscape of replicative DNA polymerase usage in the human genome

Author

Listed:
  • Eri Koyanagi

    (Tohoku University)

  • Yoko Kakimoto

    (Tohoku University)

  • Tamiko Minamisawa

    (Japanese Foundation for Cancer Research)

  • Fumiya Yoshifuji

    (Tohoku University)

  • Toyoaki Natsume

    (Research Organization of Information and Systems (ROIS)
    The Graduate University for Advanced Studies (SOKENDAI)
    Research Center for Genome & Medical Sciences, Tokyo Metropolitan Institute of Medical Science)

  • Atsushi Higashitani

    (Tohoku University)

  • Tomoo Ogi

    (Nagoya University)

  • Antony M. Carr

    (University of Sussex)

  • Masato T. Kanemaki

    (Research Organization of Information and Systems (ROIS)
    The Graduate University for Advanced Studies (SOKENDAI)
    The University of Tokyo)

  • Yasukazu Daigaku

    (Tohoku University
    Japanese Foundation for Cancer Research)

Abstract

The division of labour among DNA polymerase underlies the accuracy and efficiency of replication. However, the roles of replicative polymerases have not been directly established in human cells. We developed polymerase usage sequencing (Pu-seq) in HCT116 cells and mapped Polε and Polα usage genome wide. The polymerase usage profiles show Polε synthesises the leading strand and Polα contributes mainly to lagging strand synthesis. Combining the Polε and Polα profiles, we accurately predict the genome-wide pattern of fork directionality plus zones of replication initiation and termination. We confirm that transcriptional activity contributes to the pattern of initiation and termination and, by separately analysing the effect of transcription on co-directional and converging forks, demonstrate that coupled DNA synthesis of leading and lagging strands is compromised by transcription in both co-directional and convergent forks. Polymerase uncoupling is particularly evident in the vicinity of large genes, including the two most unstable common fragile sites, FRA3B and FRA3D, thus linking transcription-induced polymerase uncoupling to chromosomal instability. Together, our result demonstrated that Pu-seq in human cells provides a powerful and straightforward methodology to explore DNA polymerase usage and replication fork dynamics.

Suggested Citation

  • Eri Koyanagi & Yoko Kakimoto & Tamiko Minamisawa & Fumiya Yoshifuji & Toyoaki Natsume & Atsushi Higashitani & Tomoo Ogi & Antony M. Carr & Masato T. Kanemaki & Yasukazu Daigaku, 2022. "Global landscape of replicative DNA polymerase usage in the human genome," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34929-8
    DOI: 10.1038/s41467-022-34929-8
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    References listed on IDEAS

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