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

Gourish Mondal; Meredith Stevers; Benjamin Goode; Alan Ashworth; David A Solomon

doi:10.1038/s41467-019-09659-z

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.

Authors

Gourish Mondal¹, Meredith Stevers¹, Benjamin Goode¹, Alan Ashworth^{2

3}, David A Solomon^{4

5}

Affiliations

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.

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*
Cohesins
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*

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding