Sister Chromatid Cohesion: A Multilayered Regulatory Network Beyond the Cohesin Ring

Sister chromatid cohesion, mediated by the cohesin complex, ensures faithful chromosome segregation by providing the mechanical resistance required for bipolar spindle attachment. While the cohesin ring serves as the central executor, cohesion is regulated by a remarkably intricate multi-layered network extending far beyond the core complex. This review synthesizes current understanding of cohesion by integrating classical cohesin-centric regulation with emerging evidence implicating diverse non-cohesin factors, including DNA and RNA helicases, spliceosome components, microtubule-associated proteins, and post-translational modifications. We also examine the often-overlooked contribution of DNA catenation to sister chromatid association and discuss how kinase-phosphatase networks, chaperones, and non-coding RNAs coordinate cohesion establishment, maintenance, and dissolution. Throughout this review, we emphasize that the cohesin complex remains the central mediator; the additional layers discussed here modulate, stabilize, or complement its function rather than replacing it. By integrating these diverse layers into a unified framework, we highlight unresolved questions and provide a roadmap for future investigations into the molecular mechanisms that ensure genomic stability.