Scc2Scc4

Scc2-Scc4 is the loader complex for the cohesin ring in eukaryotic cells. It is essential for establishing sister chromatid cohesion by facilitating the topological loading of cohesin onto chromatin, which in turn supports chromosome segregation, DNA repair, and genome organization.

The complex is a heterodimer consisting of two subunits: Scc2, also known as NIPBL in vertebrates, and Scc4, also known as MAU2. The Scc2-Scc4 complex is highly conserved from yeast to humans, and the two subunits function together to recruit cohesin to DNA and stimulate the loading process.

Mechanistically, Scc2-Scc4 binds to chromatin and interacts with the cohesin complex, promoting opening of the cohesin ring and engagement with DNA. Through this interaction, the ATPase activity of the Smc1/Smc3 heads is stimulated, enabling cohesin to encircle two sister DNA strands. Once loaded, cohesin establishes cohesive links between sister chromatids, providing a physical basis for accurate chromosome alignment and segregation during mitosis and meiosis. Loading is most active in early S phase and occurs at chromatin sites such as replication origins, often in coordination with other cohesin regulators.

Regulation of Scc2-Scc4 activity is coordinated with the cell cycle and chromatin state, ensuring timely and context-specific loading of cohesin. In humans, mutations in NIPBL, the Scc2 ortholog, cause Cornelia de Lange syndrome, highlighting the complex’s importance for development and genomic stability.

Overall, Scc2-Scc4 acts as the critical initiator of cohesin loading, linking chromatin engagement to the cohesion and organization of the genome.