Lamin B1-dependent regulation of human separase in mitosis.

Separase plays central roles in chromosome separation during mitosis and in the centrosome duplication cycle. Tight control of separase activity is required to prevent unscheduled resolution of sister chromatid cohesion and centrosome aberrations, thereby maintaining genome stability. In mammals, despite their disassembly during early mitosis, some nuclear envelope components have mitotic roles, but the links with separase activity remain unexplored. Here, we uncover a novel mechanism of separase regulation involving lamin B1, a key nuclear envelope factor. We show that separase and lamin B1 associate preferentially during early mitotic stages. Importantly, lamin B1 depletion leads to an increase in separase recruitment to chromosomes together with premature chromatid separation, a phenotype reminiscent of separase overexpression. Conversely, similar to separase depletion, lamin B1 overexpression induces diplochromosome formation, together with centrosome amplification, phenotypes consistent with impaired sister chromatid separation. Importantly, increasing separase levels prevents lamin B1-induced centrosome aberrations, suggesting a separase defect at their origin. Indeed, we show that overexpression of lamin B1 leads to a decrease in the recruitment of separase to chromosomes and a delay in its activity. Taken together, this study unveils a novel mechanism of separase regulation involving the nuclear envelope factor lamin B1 that is critical for genome integrity.