The cohesin complex prevents Myc-induced replication stress

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• The cohesin complex plays a crucial role in genome stability and is frequently mutated in various cancers and cohesinopathies.
• Cohesin deficiencies are associated with transcriptional dysregulation, particularly affecting the Myc oncogene and its downstream targets.

Purpose of the Study:

• To investigate the dependency of cohesin's cell cycle control functions on Myc expression and activity.
• To elucidate the precise role of cohesins in managing Myc-driven transcriptional programs and DNA replication.

Main Methods:

• Silencing of the RAD21 subunit to inactivate the cohesin complex.
• Ectopic activation of Myc in RAD21-depleted cells.
• Analysis of cell cycle progression, Myc target gene transcription, and replication fork dynamics.

Main Results:

• Cohesin inactivation caused cell cycle arrest, impaired Myc target gene transcription, and led to fewer, unidirectional replication forks.
• Ectopic Myc expression in cohesin-deficient cells rescued transcription and initiated S-phase entry but caused replicative stress and DNA damage.
• Cohesin complex is dispensable for Myc-dependent transcription but essential for preventing Myc-induced replicative stress.

Conclusions:

• Cohesins are critical for preventing Myc-induced replicative stress and DNA damage, rather than for Myc-dependent transcription itself.
• A feed-forward regulatory loop exists where cohesins modulate Myc levels, controlling S-phase entry and mitigating replicative stress.