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DNA polymerase ε harmonizes topological states and R-loops formation to maintain genome integrity in Arabidopsis

Author

Listed:
  • Qin Li

    (Tsinghua University)

  • Jincong Zhou

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences)

  • Shuai Li

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences)

  • Weifeng Zhang

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences)

  • Yingxue Du

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences)

  • Kuan Li

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences
    Chinese Institute for Brain Research)

  • Yingxiang Wang

    (College of Life Science, South China Agricultural University, Guangdong Laboratory for Lingnan Morden Agriculture
    Fudan University)

  • Qianwen Sun

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences)

Abstract

Genome topology is tied to R-loop formation and genome stability. However, the regulatory mechanism remains to be elucidated. By establishing a system to sense the connections between R-loops and genome topology states, we show that inhibiting DNA topoisomerase 1 (TOP1i) triggers the global increase of R-loops (called topoR-loops) and DNA damages, which are exacerbated in the DNA damage repair-compromised mutant atm. A suppressor screen identifies a mutation in POL2A, the catalytic subunit of DNA polymerase ε, rescuing the TOP1i-induced topoR-loop accumulation and genome instability in atm. Importantly we find that a highly conserved junction domain between the exonuclease and polymerase domains in POL2A is required for modulating topoR-loops near DNA replication origins and facilitating faithful DNA replication. Our results suggest that DNA replication acts in concert with genome topological states to fine-tune R-loops and thereby maintain genome integrity, revealing a likely conserved regulatory mechanism of TOP1i resistance in chemotherapy for ATM-deficient cancers.

Suggested Citation

  • Qin Li & Jincong Zhou & Shuai Li & Weifeng Zhang & Yingxue Du & Kuan Li & Yingxiang Wang & Qianwen Sun, 2023. "DNA polymerase ε harmonizes topological states and R-loops formation to maintain genome integrity in Arabidopsis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43680-7
    DOI: 10.1038/s41467-023-43680-7
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    References listed on IDEAS

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    1. Zaida Vergara & María S. Gomez & Bénédicte Desvoyes & Joana Sequeira-Mendes & Kinda Masoud & Celina Costas & Sandra Noir & Elena Caro & Victoria Mora-Gil & Pascal Genschik & Crisanto Gutierrez, 2023. "Distinct roles of Arabidopsis ORC1 proteins in DNA replication and heterochromatic H3K27me1 deposition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Gabriel Balmus & Domenic Pilger & Julia Coates & Mukerrem Demir & Matylda Sczaniecka-Clift & Ana C. Barros & Michael Woods & Beiyuan Fu & Fengtang Yang & Elisabeth Chen & Matthias Ostermaier & Tatjana, 2019. "ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
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    Cited by:

    1. Weifeng Zhang & Zhuo Yang & Wenjie Wang & Qianwen Sun, 2024. "Primase promotes the competition between transcription and replication on the same template strand resulting in DNA damage," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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