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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月10日

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  • Qinfu Chen,
  • Xueying Yuan,
  • Miao Shi,
  • Xinyu Zhou,
  • Shukai Zhu,
  • Weiguo Lu,
  • Haiyan Yan,
  • Fangwei Wang

摘要

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.