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

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 KRAS(G12V) expression in untransformed cells triggers H3K27me3 and HP1-associated chromatin compaction...

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Autores principales: Igarashi, Taichi, Mazevet, Marianne, Yasuhara, Takaaki, Yano, Kimiyoshi, Mochizuki, Akifumi, Nishino, Makoto, Yoshida, Tatsuya, Yoshida, Yukihiro, Takamatsu, Nobuhiko, Yoshimi, Akihide, Shiraishi, Kouya, Horinouchi, Hidehito, Kohno, Takashi, Hamamoto, Ryuji, Adachi, Jun, Zou, Lee, Shiotani, Bunsyo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10435487/
https://www.ncbi.nlm.nih.gov/pubmed/37591859
http://dx.doi.org/10.1038/s41467-023-40578-2
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author Igarashi, Taichi
Mazevet, Marianne
Yasuhara, Takaaki
Yano, Kimiyoshi
Mochizuki, Akifumi
Nishino, Makoto
Yoshida, Tatsuya
Yoshida, Yukihiro
Takamatsu, Nobuhiko
Yoshimi, Akihide
Shiraishi, Kouya
Horinouchi, Hidehito
Kohno, Takashi
Hamamoto, Ryuji
Adachi, Jun
Zou, Lee
Shiotani, Bunsyo
author_facet Igarashi, Taichi
Mazevet, Marianne
Yasuhara, Takaaki
Yano, Kimiyoshi
Mochizuki, Akifumi
Nishino, Makoto
Yoshida, Tatsuya
Yoshida, Yukihiro
Takamatsu, Nobuhiko
Yoshimi, Akihide
Shiraishi, Kouya
Horinouchi, Hidehito
Kohno, Takashi
Hamamoto, Ryuji
Adachi, Jun
Zou, Lee
Shiotani, Bunsyo
author_sort Igarashi, Taichi
collection PubMed
description 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 KRAS(G12V) 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 KRAS(G12V)-induced replication stress to expand replication stress-tolerant cells (RSTCs). PrimPol is phosphorylated at Ser255, a potential Chk1 substrate site, under KRAS(G12V)-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.
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spelling pubmed-104354872023-08-19 An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress Igarashi, Taichi Mazevet, Marianne Yasuhara, Takaaki Yano, Kimiyoshi Mochizuki, Akifumi Nishino, Makoto Yoshida, Tatsuya Yoshida, Yukihiro Takamatsu, Nobuhiko Yoshimi, Akihide Shiraishi, Kouya Horinouchi, Hidehito Kohno, Takashi Hamamoto, Ryuji Adachi, Jun Zou, Lee Shiotani, Bunsyo Nat Commun Article 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 KRAS(G12V) 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 KRAS(G12V)-induced replication stress to expand replication stress-tolerant cells (RSTCs). PrimPol is phosphorylated at Ser255, a potential Chk1 substrate site, under KRAS(G12V)-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. Nature Publishing Group UK 2023-08-17 /pmc/articles/PMC10435487/ /pubmed/37591859 http://dx.doi.org/10.1038/s41467-023-40578-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Igarashi, Taichi
Mazevet, Marianne
Yasuhara, Takaaki
Yano, Kimiyoshi
Mochizuki, Akifumi
Nishino, Makoto
Yoshida, Tatsuya
Yoshida, Yukihiro
Takamatsu, Nobuhiko
Yoshimi, Akihide
Shiraishi, Kouya
Horinouchi, Hidehito
Kohno, Takashi
Hamamoto, Ryuji
Adachi, Jun
Zou, Lee
Shiotani, Bunsyo
An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress
title An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress
title_full An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress
title_fullStr An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress
title_full_unstemmed An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress
title_short An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress
title_sort atr-primpol pathway confers tolerance to oncogenic kras-induced and heterochromatin-associated replication stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10435487/
https://www.ncbi.nlm.nih.gov/pubmed/37591859
http://dx.doi.org/10.1038/s41467-023-40578-2
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