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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. Aris A. Polyzos & Ana Cheong & Jung Hyun Yoo & Lana Blagec & Sneh M. Toprani & Zachary D. Nagel & Cynthia T. McMurray, 2024. "Base excision repair and double strand break repair cooperate to modulate the formation of unrepaired double strand breaks in mouse brain," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. 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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