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

Nat Commun. 2023 Aug 17;14(1):4991. doi: 10.1038/s41467-023-40578-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Chromatin
  • DNA Primase
  • DNA-Directed DNA Polymerase
  • Genomic Instability
  • Heterochromatin* / genetics
  • Humans
  • Multifunctional Enzymes
  • Proto-Oncogene Proteins p21(ras)* / genetics


  • Ataxia Telangiectasia Mutated Proteins
  • ATR protein, human
  • Chromatin
  • DNA Primase
  • DNA-Directed DNA Polymerase
  • Heterochromatin
  • KRAS protein, human
  • Multifunctional Enzymes
  • PrimPol protein, human
  • Proto-Oncogene Proteins p21(ras)