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-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.
Highlights
Cohesin is a multiprotein ring that is responsible for cohesion of sister chromatids and formation of DNA loops to regulate gene expression
Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids
While cohesin is known to be loaded onto chromatin immediately following cytokinesis at the completion of mitosis, it is during DNA replication in S-phase when this pool of cohesin concatenates sister chromatids to establish cohesion[9,10,11]
Summary
Cohesin is a multiprotein ring that is responsible for cohesion of sister chromatids and formation of DNA loops to regulate gene expression. 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. The cohesin subunits form a ring-shaped structure that encircles chromatin, which is loaded onto chromatin in early G1 phase of the cell cycle immediately following cytokinesis and concatenates sister chromatids during DNA replication in S phase. Genomewide transcriptional profiling in cells derived from Cornelia de Lange syndrome patients with NIPBL or SMC1A mutations versus normal subjects has revealed a conserved pattern of transcriptional dysregulation[22,23] As a result, these cohesinopathy syndromes are widely regarded to result from deregulated gene expression during development
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