Repression of Transcription at DNA Breaks Requires Cohesin throughout Interphase and Prevents Genome Instability

Area of Science:

• Molecular Biology
• Cancer Biology
• Genetics

Background:

• Cohesin protein subunits are frequently mutated in various cancers, suggesting a tumor suppressor role.
• The established function of cohesin is mediating sister chromatid cohesion, crucial for accurate chromosome segregation during cell division.
• However, sister chromatid cohesion is not consistently disrupted in all cancer cells, hinting at alternative functions of cohesin.

Purpose of the Study:

• To investigate the previously unknown functions of cohesin in cancer, beyond its role in sister chromatid cohesion.
• To determine if cohesin plays a role in regulating gene expression at sites of DNA damage.
• To explore the implications of cohesin dysfunction in cancer development and genome instability.

Main Methods:

• Investigated cohesin's role in transcription regulation at DNA double-strand breaks (DSBs) across different cell cycle phases.
• Utilized a cancer-associated SA2 mutation to differentiate between cohesin's roles in sister chromatid cohesion and transcriptional repression at DSBs.
• Analyzed genome-wide mutational patterns in cancer samples lacking SA2 to correlate with the identified pathway.

Main Results:

• Cohesin is essential for repressing transcription at DNA double-strand breaks (DSBs) throughout interphase, a function distinct from sister chromatid cohesion.
• A cancer-associated SA2 mutation supports sister chromatid cohesion but fails to repress transcription at DSBs.
• Failure to repress transcription at DSBs results in large-scale genome rearrangements, and SA2-deficient cancers exhibit mutational signatures consistent with this defect.

Conclusions:

• Cohesin possesses a novel tumor suppressor function: repressing transcription at DNA double-strand breaks.
• Dysfunctional cohesin, specifically impaired transcriptional repression at DSBs due to mutations like SA2, contributes to genome instability and cancer.
• This discovery provides critical insights into why cohesin subunits are frequently lost or mutated in cancer.