Dual Roads of CENP-A for Centromere Identification

Faithful chromosome segregation requires the kinetochore, a macromolecular protein complex that assembles on centromeric chromatin. In vertebrates, centromere identity is epigenetically defined by the histone H3 variant CENP-A, whose nucleosomes are replenished during early G1 phase through a cell cycle-regulated deposition mechanism. The CENP-A chaperone HJURP is recruited to centromeres via the Mis18 complex to enable CENP-A incorporation (Mis18C pathway). Recent genetic analyses in chicken cells, however, revealed an additional, independent recruitment route via direct HJURP-CENP-C interaction (CENP-C pathway). Structural studies show that CENP-C and the Mis18C subunit KNL2/M18BP1 engage pre-existing CENP-A nucleosomes at different surfaces of the Constitutive Centromere-Associated Network (CCAN), constraining the spatial coordinates where new CENP-A is incorporated. This review summarizes current understanding of HJURP recruitment mechanisms for vertebrate CENP-A deposition and proposes that this structure-defined deposition geometry underlies epigenetic self-propagation of centromere positional information by maintaining proper CCAN spacing across cell divisions.