A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers

Nat Commun. 2019 Apr 11;10(1):1686. doi: 10.1038/s41467-019-09659-z.


Cohesin is a multiprotein ring that is responsible for cohesion of sister chromatids and formation of DNA loops to regulate gene expression. Genomic analyses have identified that the cohesin subunit STAG2 is frequently inactivated by mutations in cancer. However, the reason STAG2 mutations are selected during tumorigenesis and strategies for therapeutically targeting mutant cancer cells are largely unknown. Here we show that STAG2 is essential for DNA replication fork progression, whereby STAG2 inactivation in non-transformed cells leads to replication fork stalling and collapse with disruption of interaction between the cohesin ring and the replication machinery as well as failure to establish SMC3 acetylation. As a consequence, STAG2 mutation confers synthetic lethality with DNA double-strand break repair genes and increased sensitivity to select cytotoxic chemotherapeutic agents and PARP or ATR inhibitors. These studies identify a critical role for STAG2 in replication fork procession and elucidate a potential therapeutic strategy for cohesin-mutant cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Nuclear / genetics
  • Antigens, Nuclear / metabolism*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Carcinogenesis / genetics
  • Cell Cycle Proteins / genetics*
  • Cell Line, Tumor
  • Chromatids / metabolism
  • Chromosomal Proteins, Non-Histone / genetics*
  • DNA Breaks, Double-Stranded
  • DNA Replication
  • Drug Screening Assays, Antitumor
  • Gene Knockout Techniques
  • Humans
  • Mutagenesis
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Poly(ADP-ribose) Polymerases / metabolism
  • RNA, Small Interfering / metabolism
  • Recombinational DNA Repair
  • Synthetic Lethal Mutations*


  • Antigens, Nuclear
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Poly(ADP-ribose) Polymerase Inhibitors
  • RNA, Small Interfering
  • STAG2 protein, human
  • cohesins
  • Poly(ADP-ribose) Polymerases
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins