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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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    as
    1. Julien N. Bianco & Valérie Bergoglio & Yea-Lih Lin & Marie-Jeanne Pillaire & Anne-Lyne Schmitz & Julia Gilhodes & Amelie Lusque & Julien Mazières & Magali Lacroix-Triki & Theodoros I. Roumeliotis & Jy, 2019. "Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Jianquan Xu & Hongqiang Ma & Hongbin Ma & Wei Jiang & Christopher A. Mela & Meihan Duan & Shimei Zhao & Chenxi Gao & Eun-Ryeong Hahm & Santana M. Lardo & Kris Troy & Ming Sun & Reet Pai & Donna B. Sto, 2020. "Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    3. Jirina Bartkova & Zuzana Hořejší & Karen Koed & Alwin Krämer & Frederic Tort & Karsten Zieger & Per Guldberg & Maxwell Sehested & Jahn M. Nesland & Claudia Lukas & Torben Ørntoft & Jiri Lukas & Jiri B, 2005. "DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis," Nature, Nature, vol. 434(7035), pages 864-870, April.
    4. Ann Liza Piberger & Akhil Bowry & Richard D. W. Kelly & Alexandra K. Walker & Daniel González-Acosta & Laura J. Bailey & Aidan J. Doherty & Juan Méndez & Joanna R. Morris & Helen E. Bryant & Eva Peter, 2020. "PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    5. Panagiotis Kotsantis & Lara Marques Silva & Sarah Irmscher & Rebecca M. Jones & Lisa Folkes & Natalia Gromak & Eva Petermann, 2016. "Increased global transcription activity as a mechanism of replication stress in cancer," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    6. Hyoung Kim & Haineng Xu & Erin George & Dorothy Hallberg & Sushil Kumar & Veena Jagannathan & Sergey Medvedev & Yasuto Kinose & Kyle Devins & Priyanka Verma & Kevin Ly & Yifan Wang & Roger A. Greenber, 2020. "Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    7. Ludmil B. Alexandrov & Jaegil Kim & Nicholas J. Haradhvala & Mi Ni Huang & Alvin Wei Tian Ng & Yang Wu & Arnoud Boot & Kyle R. Covington & Dmitry A. Gordenin & Erik N. Bergstrom & S. M. Ashiqul Islam , 2020. "The repertoire of mutational signatures in human cancer," Nature, Nature, vol. 578(7793), pages 94-101, February.
    8. Jirina Bartkova & Nousin Rezaei & Michalis Liontos & Panagiotis Karakaidos & Dimitris Kletsas & Natalia Issaeva & Leandros-Vassilios F. Vassiliou & Evangelos Kolettas & Katerina Niforou & Vassilis C. , 2006. "Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints," Nature, Nature, vol. 444(7119), pages 633-637, November.
    9. Morgane Macheret & Thanos D. Halazonetis, 2018. "Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress," Nature, Nature, vol. 555(7694), pages 112-116, March.
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