The Roles of Histone Post-Translational Modifications in the Formation and Function of a Mitotic Chromosome

Abstract

During mitosis, many cellular structures are organized to segregate the replicated genome to the daughter cells. Chromatin is condensed to shape a mitotic chromosome. A multiprotein complex known as kinetochore is organized on a specific region of each chromosome, the centromere, which is defined by the presence of a histone H3 variant called CENP-A. The cytoskeleton is re-arranged to give rise to the mitotic spindle that binds to kinetochores and leads to the movement of chromosomes. How chromatin regulates different activities during mitosis is not well known. The role of histone post-translational modifications (HPTMs) in mitosis has been recently revealed. Specific HPTMs participate in local compaction during chromosome condensation. On the other hand, HPTMs are involved in CENP-A incorporation in the centromere region, an essential activity to maintain centromere identity. HPTMs also participate in the formation of regulatory protein complexes, such as the chromosomal passenger complex (CPC) and the spindle assembly checkpoint (SAC). Finally, we discuss how HPTMs can be modified by environmental factors and the possible consequences on chromosome segregation and genome stability.

Keywords: arsenic; centromere; chromosome condensation; histones; kinetochore; mitosis; nickel.

Figure 1

HPTMs in chromosome condensation. Condensins participate in the axial shortening of chromosomes while histone modifications allow the local compaction. H3 is phosphorylated in the serine 10 along all the chromosomes. This modification recruits Hst2p, which deacetylates H4K16 by inducing local nucleosome joining and local chromatin compaction. H3T118 also participates in chromosome condensation, and its distribution is preferentially in the pericentromeric chromatin, but its function is still unknown.

Figure 2

HPTM-dependent CPC recruitment. H3T3 and H2AT120 phosphorylations, by Haspin and BUB1, respectively, are two key HPTMs necessary for the recruitment of the CPC to centromeres. The coincidence of these marks on mitotic chromosomes specifies the site of CPC localization. Survivin binds to H3T3ph, conveying the other components of the complex, while Shugoshin binds to H2AT120, acting as an adaptor between this mark and Borealin. A phosphorylation-dependent positive feedback loop occurs between Aurora B and Haspin kinases, reinforcing the CPC recruitment pathway.

Figure 3

Roles of HPTMs in CENP-A incorporation. In every cell cycle, half of the CENP-A nucleosomes from each centromere are loaded onto the nascent DNA strand during DNA replication. As a result, G2 centromeres show half of the CENP-A nucleosomes that G1 centromeres have. The incorporation of new CENP-A nucleosomes remains inhibited during G2 and early mitosis by specific phosphorylations on histone and non-histone proteins (upper panel). These phosphorylations prevent the formation of key complexes for CENP-A incorporation, such as the Mis18BP1 complex. However, CENP-A nucleosome levels are replenished during late mitosis/early G1. The methylation, acetylation, and ubiquitination of different histones are required during the process (middle and lower panel). This cascade of events involves at least two feedback loops, ultimately leading to increased CENP-A incorporation. HPTMs are depicted in green, proteins and RNA in pink, and processes in grey.