An ATR-PrimPol Pathway Confers Tolerance to Oncogenic KRAS-induced and Heterochromatin-associated Replication Stress

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Aug 17

PMID 37591859

Authors

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

Bunsyo Shiotani

Affiliations

Soon will be listed here.

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 KRAS 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-induced replication stress to expand replication stress-tolerant cells (RSTCs). PrimPol is phosphorylated at Ser255, a potential Chk1 substrate site, under KRAS-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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