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

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

Author information

1
Department of Pathology, University of California, San Francisco, CA, 94143, USA.
2
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA.
3
Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, CA, 94158, USA.
4
Department of Pathology, University of California, San Francisco, CA, 94143, USA. david.solomon@ucsf.edu.
5
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA. david.solomon@ucsf.edu.

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.

PMID:
30975996
PMCID:
PMC6459917
DOI:
10.1038/s41467-019-09659-z
[Indexed for MEDLINE]
Free PMC Article

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