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Phosphorylation and DNA Binding of HJURP Determine Its Centromeric Recruitment and Function in CenH3 CENP-A Loading

Abstract : Centromeres, epigenetically defined by the presence of the histone H3 variant CenH3, are essential for ensuring proper chromosome segregation. In mammals , centromeric CenH3 CENP-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 nonphosphorylat-able HJURP mutant localizes prematurely to centro-meres in S and G2 phase. This unregulated targeting causes a premature loading of CenH3 CENP-A at centromeres, and cell-cycle delays ensue. Once recruited to centromeres, HJURP functions to promote CenH3 CENP-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 CenH3 CENP-A loading.
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Sebastian Müller, Rocio Montes de Oca, Nicolas Lacoste, Florent Dingli, Damarys Loew, et al.. Phosphorylation and DNA Binding of HJURP Determine Its Centromeric Recruitment and Function in CenH3 CENP-A Loading. Cell Reports, Elsevier Inc, 2014, 8 (1), pp.190-203. ⟨10.1016/j.celrep.2014.06.002⟩. ⟨hal-01312876⟩

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