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STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers
Petra van der Lelij1, Joseph A Newman2, Simone Lieb3
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria.
Abstract:
The cohesin subunit STAG2 has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed a synthetic lethal interaction between STAG2 and its paralog STAG1 To systematically probe genetic vulnerabilities in the absence of STAG2, we have performed genome-wide CRISPR screens in isogenic cell lines and identified STAG1 as the most prominent and selective dependency of STAG2-deficient cells. Using an inducible degron system, we show that chemical genetic degradation of STAG1 protein results in the loss of sister chromatid cohesion and rapid cell death in STAG2-deficient cells, while sparing STAG2-wild-type cells. Biochemical assays and X-ray crystallography identify STAG1 regions that interact with the RAD21 subunit of the cohesin complex. STAG1 mutations that abrogate this interaction selectively compromise the viability of STAG2-deficient cells. Our work highlights the degradation of STAG1 and inhibition of its interaction with RAD21 as promising therapeutic strategies. These findings lay the groundwork for the development of STAG1-directed small molecules to exploit synthetic lethality in STAG2-mutated tumors.
Insights
Targeting STAG1 offers a new therapeutic strategy for STAG2-mutated cancers. Depleting STAG1 protein causes cell death in STAG2-deficient cells, showing synthetic lethality.
Area of Science:
- Cancer Biology
- Molecular Genetics
- Chromosomal Instability
Background:
- The cohesin subunit STAG2 is a tumor suppressor frequently inactivated in human cancers.
- Previous studies suggest a synthetic lethal interaction between STAG2 and its paralog STAG1.
Purpose of the Study:
- To systematically identify genetic vulnerabilities in STAG2-deficient cells.
- To explore STAG1 as a potential therapeutic target in STAG2-mutated cancers.
Main Methods:
- Genome-wide CRISPR screens in isogenic cell lines.
- Inducible degron system for STAG1 protein degradation.
- Biochemical assays and X-ray crystallography to map STAG1-RAD21 interactions.
Main Results:
- STAG1 was identified as a key dependency in STAG2-deficient cells.
- Chemical genetic degradation of STAG1 induced sister chromatid cohesion loss and cell death in STAG2-deficient cells.
- STAG1 mutations disrupting RAD21 interaction selectively impaired viability of STAG2-deficient cells.
Conclusions:
- STAG1 is a critical vulnerability in STAG2-deficient cancers.
- Targeting STAG1 degradation or its interaction with RAD21 represents a promising therapeutic strategy.
- Development of STAG1-directed small molecules could exploit synthetic lethality in STAG2-mutated tumors.
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