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

ABSTRACT: 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-s

SUBMITTER: Mondal G 

PROVIDER: S-EPMC6459917 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature