KRAS致癌基因的激活是复制应激的来源，但是这种应激是如何产生的，以及癌细胞如何容忍这种应激，目前还不太清楚。在这里，我们展示了KRASG12V在未转化的细胞中的表达诱导了H3K27me3和HP1相关染色质的紧密结缩，这是一个依赖于RNA转录的过程，导致复制叉降速和细胞死亡。此外，高水平的ATR表达对于KRASG12V诱导的复制应激产生耐受是必要且足够的，以扩大具有复制应激耐受性的细胞（RSTCs）。在KRASG12V诱导的复制应激下，PrimPol在Ser255位点被磷酸化，该位点是潜在的Chk1底物位点，PrimPol在ATR/Chk1依赖的方式中促进再启动，以维持复制叉的进展和细胞存活。然而，PrimPol依赖的再启动在异染色质中产生单链DNA缺口，导致基因组不稳定性。这些结果揭示了ATR-PrimPol在使癌前细胞能够在KRAS诱导的复制应激下存活，并且在基因组不稳定性积累的同时进行克隆扩增的作用。© 2023. Springer Nature Limited.

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.© 2023. Springer Nature Limited.