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

Taichi Igarashi, Marianne Mazevet, Takaaki Yasuhara, Kimiyoshi Yano, Akifumi Mochizuki, Makoto Nishino, Tatsuya Yoshida, Yukihiro Yoshida, Nobuhiko Takamatsu, Akihide Yoshimi, Kouya Shiraishi, Hidehito Horinouchi, Takashi Kohno, Ryuji Hamamoto, Jun Adachi, Lee Zou and Bunsyo Shiotani ()
Additional contact information
Taichi Igarashi: National Cancer Center Research Institute
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
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
Kouya Shiraishi: 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
Bunsyo Shiotani: National Cancer Center Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40578-2

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