Sororin locks the DNA-exit gate of cohesin to preserve sister-chromatid cohesion

TL;DR

This paper reveals that Sororin directly locks a DNA-exit gate in the cohesin complex to maintain sister-chromatid cohesion, in addition to its known role in regulating Wapl-Pds5 interactions.

Contribution

The study identifies a novel structural role of Sororin's C-terminal region in directly stabilizing cohesin's DNA-exit gate.

Findings

Sororin's C-terminal region locks the RAD21-SMC3 interface to preserve sister-chromatid cohesion.

Disruption of Sororin's gate engagement abolishes cohesion in a Wapl-dependent manner.

Mitotic phosphorylation of Sororin selectively disrupts Pds5 binding but preserves gate engagement.

Abstract

The cohesin complex mediates sister-chromatid cohesion by topologically entrapping DNA within an SMC1-SMC3-RAD21 ring, yet how Sororin preserves cohesion beyond its known role of antagonizing Pds5 binding to the release factor Wapl has remained unclear. Here, we show that the extreme C-terminal region (CTR) of Sororin functions as a direct structural lock for cohesin’s DNA-exit gate by engaging the RAD21-SMC3 interface. Centromere-tethered Sororin-CTR fully restores cohesion after Sororin depletion, whereas constitutive chromatin tethering prevents cohesin removal, recapitulating Wapl-loss phenotypes, including impaired mitotic chromosome condensation, decatenation and segregation. Through biochemical reconstitution, AlphaFold3-guided modeling, and targeted mutagenesis, we define conserved hydrophobic and electrostatic contacts between Sororin-CTR and the RAD21-SMC3 gate, the disruption of which abolishes cohesion in a Wapl-dependent manner. Furthermore, mitotic phosphorylation of Sororin selectively disrupts Pds5 binding while leaving gate engagement intact, providing a regulated molecular switch for cohesin release. Together, these findings redefine Sororin as a dual-function regulator that both antagonizes Wapl-Pds5 and directly locks the RAD21-SMC3 exit gate to stabilize sister-chromatid cohesion while permitting its timely dissolution.

Chen et al. identify that the extreme C-terminal region of Sororin directly locks the cohesin DNA-exit gate to stabilize sister-chromatid cohesion, a mechanism distinct from its established role in antagonizing Wapl binding to Pds5.

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