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An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress

Author

Listed:
  • Taichi Igarashi

    (National Cancer Center Research Institute
    Kitasato University, Minami-ku)

  • Marianne Mazevet

    (National Cancer Center Research Institute)

  • Takaaki Yasuhara

    (Kyoto University)

  • Kimiyoshi Yano

    (National Cancer Center Research Institute)

  • Akifumi Mochizuki

    (National Cancer Center Research Institute
    Tokyo Medical and Dental University)

  • Makoto Nishino

    (National Cancer Center Research Institute)

  • Tatsuya Yoshida

    (National Cancer Center Hospital)

  • Yukihiro Yoshida

    (National Cancer Center Hospital)

  • Nobuhiko Takamatsu

    (Kitasato University, Minami-ku)

  • Akihide Yoshimi

    (Kitasato University, Minami-ku
    National Cancer Center Research Institute)

  • Kouya Shiraishi

    (National Cancer Center Research Institute
    National Cancer Center Research Institute)

  • Hidehito Horinouchi

    (National Cancer Center Hospital)

  • Takashi Kohno

    (National Cancer Center Research Institute)

  • Ryuji Hamamoto

    (National Cancer Center Research Institute)

  • Jun Adachi

    (Health and Nutrition)

  • Lee Zou

    (Harvard Medical School
    Harvard Medical School
    Duke University School of Medicine)

  • Bunsyo Shiotani

    (National Cancer Center Research Institute)

Abstract

Activation of the KRAS oncogene is a source of replication stress, but how this stress is generated and how it is tolerated by cancer cells remain poorly understood. Here we show that induction of KRASG12V expression in untransformed cells triggers H3K27me3 and HP1-associated chromatin compaction in an RNA transcription dependent manner, resulting in replication fork slowing and cell death. Furthermore, elevated ATR expression is necessary and sufficient for tolerance of KRASG12V-induced replication stress to expand replication stress-tolerant cells (RSTCs). PrimPol is phosphorylated at Ser255, a potential Chk1 substrate site, under KRASG12V-induced replication stress and promotes repriming to maintain fork progression and cell survival in an ATR/Chk1-dependent manner. However, ssDNA gaps are generated at heterochromatin by PrimPol-dependent repriming, leading to genomic instability. These results reveal a role of ATR-PrimPol in enabling precancerous cells to survive KRAS-induced replication stress and expand clonally with accumulation of genomic instability.

Suggested Citation

  • Taichi Igarashi & Marianne Mazevet & Takaaki Yasuhara & Kimiyoshi Yano & Akifumi Mochizuki & Makoto Nishino & Tatsuya Yoshida & Yukihiro Yoshida & Nobuhiko Takamatsu & Akihide Yoshimi & Kouya Shiraish, 2023. "An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40578-2
    DOI: 10.1038/s41467-023-40578-2
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