| SMC3 belongs to the structural maintenance of chromosomes family and forms, together with SMC1, the core heterodimer of the cohesin complex that organizes chromatin architecture and maintains sister chromatid pairing during the cell cycle. The protein contains N- and C-terminal globular domains that join to form an ATPase head, long antiparallel coiled-coil arms, and a central hinge that dimerizes with SMC1, while a kleisin subunit such as SCC1/RAD21 links the heads to generate a tripartite ring able to entrap DNA. ATP binding and hydrolysis at the SMC1–SMC3 heads drive conformational changes that allow the heterodimer to restructure DNA into loops with a preference for positive writhe, supporting cohesin’s ability to topologically embrace chromatin and dynamically remodel local topology. The Smc3–Scc1 interface forms a four-helix bundle between the coiled-coil emerging from the Smc3 ATPase head and helices in the N-terminal kleisin region, providing a regulated DNA entry and exit gate whose integrity is essential for stable cohesin association with chromosomes. Acetylation on conserved residues in the nucleotide-binding domain of Smc3 establishes sister chromatid cohesion during S phase by counteracting release activities and promoting the formation of cohesin populations that persist on replicated chromatids until their separation at anaphase. Through these activities, SMC3-containing cohesin complexes support accurate chromosome segregation, replication-coupled cohesion establishment, and repair-associated recombination events that depend on proper juxtaposition and alignment of sister chromatids. Alterations that impair the Smc3–Scc1 interface or disrupt the acetylation cycle reduce cohesin residence on chromatin, compromise cohesion, and disturb higher-order chromatin loop organization, affecting gene regulation and genome stability. Heterozygous SMC3 mutations identified in individuals with Cornelia de Lange–overlapping phenotypes are predicted to produce structurally intact cohesin complexes but to modify chromosome-binding dynamics, and these variants are associated with growth and developmental abnormalities that link SMC3 dosage and function to human cohesinopathies. |
