Paralogous synthetic lethality underlies genetic dependencies of the cancer-mutated gene STAG2

Area of Science:

• Genetics and Molecular Biology
• Cancer Biology
• Genomics

Background:

• The STAG2 gene is a key component of the cohesin complex, essential for mitosis.
• STAG2 mutations are prevalent in various cancers, including glioblastoma and bladder cancer.
• The complex roles of cohesin in cancer pathways like chromosome instability and gene expression present challenges in understanding STAG2's tumorigenic potential and therapeutic utility.

Purpose of the Study:

• To investigate STAG2-dependent genetic interactions across different cellular contexts using whole-genome CRISPR-Cas9 screening.
• To identify potential therapeutic vulnerabilities and understand the functional impact of STAG2 loss in cancer.

Main Methods:

• Whole-genome CRISPR-Cas9 screens were employed to identify genetic interactions dependent on STAG2.
• Three distinct cellular backgrounds were utilized to ensure broad applicability of findings.
• Genetic interaction analysis, including negative genetic interactions and synthetic lethality, was performed.

Main Results:

• STAG1, the paralog of STAG2, emerged as the sole shared negative genetic interaction across all tested cellular backgrounds.
• A paralogous synthetic lethal mechanism was identified between STAG2 and the iron regulatory gene IREB2.
• Context-dependent genetic interactions revealed factors potentially involved in alleviating cohesin loading stress.

Conclusions:

• STAG2 loss exhibits a conserved genetic interaction with STAG1, suggesting a potential therapeutic strategy targeting this paralogous relationship in STAG2-mutated cancers.
• The discovery of a synthetic lethal interaction with IREB2 provides a novel avenue for exploring STAG2-targeted therapies.
• Understanding cohesin loading stress factors may offer new insights into overcoming therapeutic resistance in cancers with STAG2 mutations.