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Published on: May 27, 2021
A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant
Gourish Mondal1, Meredith Stevers1, Benjamin Goode1
1Department of Pathology, University of California, San Francisco, CA, 94143, USA.
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.
Insights
Mutations in the cohesin subunit STAG2 disrupt DNA replication, causing cancer cell vulnerabilities. Targeting these STAG2-mutant cancers shows promise with specific DNA repair inhibitors and chemotherapies.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- Cohesin, a protein complex, is crucial for sister chromatid cohesion and gene regulation via DNA looping.
- Genomic studies reveal frequent STAG2 subunit inactivation in various cancers, but the underlying reasons and therapeutic implications remain unclear.
Purpose of the Study:
- To investigate the functional role of STAG2 in DNA replication and its implications in cancer.
- To identify potential therapeutic strategies targeting STAG2-mutant cancer cells.
Main Methods:
- Functional assays to assess DNA replication fork progression in cells with STAG2 inactivation.
- Analysis of protein interactions between cohesin and replication machinery.
- Evaluation of synthetic lethality with DNA repair genes and sensitivity to therapeutic agents.
Main Results:
- STAG2 is essential for DNA replication fork progression; its inactivation leads to stalling and collapse.
- STAG2 loss disrupts cohesin-replication machinery interaction and SMC3 acetylation.
- STAG2 mutations confer synthetic lethality with DNA double-strand break repair pathways and increase sensitivity to PARP/ATR inhibitors and certain chemotherapies.
Conclusions:
- STAG2 plays a critical role in maintaining replication fork stability.
- STAG2 inactivation presents a vulnerability exploitable for targeted cancer therapy, particularly with DNA repair inhibitors.
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