Phosphorylation and DNA Binding of HJURP Determine Its Centromeric Recruitment and Function in CenH3CENP-A Loading

• Cell-cycle-dependent recruitment of HJURP to centromeres is controlled by CDKs
• Precise phosphorylation sites in HJURP control its centromeric localization
• A DNA-binding domain lies in the central conserved domain of HJURP
• HJURP binding to DNA promotes loading of CenH3CENP-A at centromeres

SummaryCentromeres, epigenetically defined by the presence of the histone H3 variant CenH3, are essential for ensuring proper chromosome segregation. In mammals, centromeric CenH3CENP-A deposition requires its dedicated chaperone HJURP and occurs during telophase/early G1. We find that the cell-cycle-dependent recruitment of HJURP to centromeres depends on its timely phosphorylation controlled via cyclin-dependent kinases. A nonphosphorylatable HJURP mutant localizes prematurely to centromeres in S and G2 phase. This unregulated targeting causes a premature loading of CenH3CENP-A at centromeres, and cell-cycle delays ensue. Once recruited to centromeres, HJURP functions to promote CenH3CENP-A deposition by a mechanism involving a unique DNA-binding domain. With our findings, we propose a model wherein (1) the phosphorylation state of HJURP controls its centromeric recruitment in a cell-cycle-dependent manner, and (2) HJURP binding to DNA is a mechanistic determinant in CenH3CENP-A loading.

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