Cdk1: conductor of CENP-A symphony orchestra

Abstract

The inheritance of human genome through mitosis is precisely regulated by a series of tightly orchestrated events such as chromosome condensation, bi-orientated spindle formation, chromosome congression, segregation and cytokinesis. Chromosome movements during mitosis are governed by dynamic interactions of spindle microtubules with a specialized chromosome domain called centromere. Centromere provides the platform for the assembly of a protein machine named kinetochore that orchestrates accurate interaction between chromosomes and spindle microtubules during cell division. In eukaryotic organisms, the centromere is epigenetically specified by nucleosomes containing a unique histone H3 variant CENP-A, with the exception of budding yeast [1]. CENP-A orthologues present in all known eukaryotes. It is the most important epigenetic marker of centromere [2] and is required for the correct localization of most centromereand kinetochorerelated proteins [2]. CENP-A is the epigenetic marker to maintain and propagate the centromere identity, which assembles into a nucleosome together with histones H4, H2A and H2B without any known specific selection of DNA sequence [1, 2]. Centromeric chromatin is interspersed with CENP-A-nucleosomes and histone H3-containing nucleosomes, and it forms a repressive heterochromatin structure through the concerted action of various epigenetic mechanisms including histone methylation [2]. The plasticity of centromeric chromatin is crucial for the assembly of a large protein machine kinetochore that links chromosome to the spindle microtubule for mitotic segregation. Interestingly, recruitment of new CENP-A to centromere is not contemporaneous with replication of centromeric DNA in S phase. Rather, it is restricted to a brief interval in G1 immediately following mitosis in human cells [3] and slightly earlier in anaphase in the rapidly dividing Drosophila syncytial embryo. The assembly of new CENP-A nucleosomes in early G1 is dependent on CENP-C, Mis18 complex and HJURP (Holliday junction recognition protein). Among these proteins, HJURP is of great importance for CENP-A deposition as it is a CENPA-specific histone chaperone. HJURP interacts directly with CENP-A and histone H4 and recruits CENP-A to the centromere in a cell cycle-dependent manner. HJURP contains an approximately 80-amino acid CENP-A-binding domain (CBD) at the N terminus that is essential and sufficient for binding CENP-A. In addition, CENP-A contains a typical C-terminal histone fold domain, known as the centromere targeting domain (CATD), is required for interaction with HJURP [4]. In yeast, the HJURP homolog Scm3 is required for the deposition of centromeric nucleosomes. Down-regulation of HJURP impairs the deposition of newly synthesized CENP-A in mammalian cells. As a molecular chaperone of CENP-A, HJURP forms prenucleosomal complex with CENP-A/H4 heterodimer via its highly conserved Scm3 domain [4]. Recent studies show that mitotic master kinase Cdk1 phosphorylates HJURP at its C-terminal domain by which negatively regulates HJURP interaction with Mis18b and subsequent inhibits CENP-A loading in early mitosis when Cdk1 activity is high [5]. In fact, inhibition of Cdk1 resulted in premature C. Jin X. Yao (&) Anhui Key Laboratory for Cellular Dynamics & Chemical Biology, University of Science and Technology of China, Hefei 230027, China e-mail: yaoxb@ustc.edu.cn