CENP-A Ubiquitylation Is Inherited through Dimerization between Cell Divisions

• Pre-existing ubiquitylated CENP-A is required to recruit new CENP-A to centromeres
• In order to be inherited, CENP-A ubiquitylation requires CENP-A dimerization
• CENP-A ubiquitylation determines centromere location through dimerization
• Overexpression of a monoubiquitin-fused CENP-A mutant induces neocentromere formation

SummaryThe presence of chromatin containing the histone H3 variant CENP-A dictates the location of the centromere in a DNA sequence-independent manner. But the mechanism by which centromere inheritance occurs is largely unknown. We previously reported that CENP-A K124 ubiquitylation, mediated by CUL4A-RBX1-COPS8 E3 ligase activity, is required for CENP-A deposition at the centromere. Here, we show that pre-existing ubiquitylated CENP-A is necessary for recruitment of newly synthesized CENP-A to the centromere and that CENP-A ubiquitylation is inherited between cell divisions. In vivo and in vitro analyses using dimerization mutants and dimerization domain fusion mutants revealed that the inheritance of CENP-A ubiquitylation requires CENP-A dimerization. Therefore, we propose models in which CENP-A ubiquitylation is inherited and, through dimerization, determines centromere location. Consistent with this model is our finding that overexpression of a monoubiquitin-fused CENP-A mutant induces neocentromeres at noncentromeric regions of chromosomes.

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