Global landscape of replicative DNA polymerase usage in the human genome

Eri Koyanagi, Yoko Kakimoto, Tamiko Minamisawa, Fumiya Yoshifuji, Toyoaki Natsume, Atsushi Higashitani, Tomoo Ogi, Antony M. Carr, Masato T. Kanemaki and Yasukazu Daigaku ()
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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)
Atsushi Higashitani: Tohoku University
Tomoo Ogi: Nagoya University
Antony M. Carr: University of Sussex
Masato T. Kanemaki: Research Organization of Information and Systems (ROIS)
Yasukazu Daigaku: Tohoku University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34929-8

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