Histone phosphorylation during mitosis

In order to replicate, cells need to duplicate their chromosomes and then separate the identical sets before the cell divides into two. The process of separation of these identical sets of chromosomes is called mitosis. The so-called histones are proteins that package DNA and are part of chromosomes. At the end of mitosis, the holoenzyme complex of PPl and the histone H3-PPl-targeting subunit Repo-Man dephosphorylates histone H3 on threonine 3 (H3T3), which is phosphorylated during mitosis [29]. The effects of PDP3-induced PPl activation on the phosphorylation status of H3T3 and downstream effects were systematically studied [16]. 

Histone phosphorylation is a common posttranslational modification fond in histones, primarily on the N-terminal tails. Phosphorylation sites include serine and threonine residues, tyrosine phosphorylation has not been observed so far. Some phosphorylation events occur locally whereas others occur globally throughout all chromosomes during specific events like mitosis. Histone phosphorylation is catalyzed by kinases. Removal of the phosphoryl groups is catalyzed by phosphatases. 

Wei Y, Mizzen CA, Cook RG, Gorovsky MA, Allis CD (1998) Phosphorylation of histone H3 at serine 10 is correlated with chromosome condensation during mitosis and meiosis in Tetrahymena. Proc Natl Acad Sci U S A 95 7480-7484... 

Barber CM et al., report that histone H2A is highly phosphorylated at Serine 1 residues during mitosis in the worm, fly, and mammalian cells (Barber et al, 2004). This phosphorylation by MSKl negatively regulated transcription on chromatin templates (Zhang et al, 2004). 

Histone H3 (Til) phosphorylation occurs during mitosis by Dlk/ZIP kinase (Dlk Death-associated protein (DAP)-like kinase, ZIP Zipper interacting protein kinase) (Preuss et al, 2003) (Table 1). Histone H3 at Serine 28 is phosphorylated by Aurora B kinase at mitosis and this phosphorylation coincides with chromosome condensation (Goto et al., 1999, Goto et al, 2002) (Fig. 2), (Table 1). Histone H3 (S28) phosphorylation initiates at prophase, whereas histone H3 (SIO) phosphorylation initiates during the late G2 phase (Hendzel et al, 1997). 

We have discussed phosphorylation of histone H3, which has been studied in many organisms. Phosphorylation of histone H3 (SIO) has two opposite main functions. One is necessary to initiate chromosome condensation during mitosis and meiosis, while the other is transcriptional activation. Current evidence shows that a combination of phosphorylation of H3 (SIO) and methylation of H3 (K9) or acetylation H3 (K9, K14) play important roles in these phenomena including cell cycle related chromosome dynamics and transcriptional activation. These results suggest that a combination of different histone modifications excute different biological outcomes. 

Recent studies have demonstrated that histone H4 (SI) phosphorylation is also a key role in the response to DNA double-strand breaks, cell-cycle progression and gene expression. In particular, this modification may have important roles during mitosis and S-phase-associated events in the cell-cycle and its phosphorylation found on newly synthesized histones during S-phase. However this phosphorylated residue is a novel histone modification site, and the details of this mechanism will be made evident by future experimentation. 

H3 differs from the other core histones in that it is phosphorylated to a greater extent during mitosis than during other parts of the cell cycle [4,30] (Fig. 4). During... 

Tora L. 2008. Histone H3 tails containing dimethylated lysine and adjacent phosphorylated serine modifications adopt a specific conformation during mitosis and meiosis. Mol Cell Biol 28(5) 1739-1754. 

Marks, D. B., Paik, W. K., and Borun, T. W., 1973, The relationship of histone phosphorylation to deoxyribonucleic acid replication and mitosis during the HeLa S-3 cell cycle, /. Biol Chem. 248 5660. 

Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalh T, Brinkley BR, Bazett-Jones DP, Allis CD (1997) Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma 106(6) 348—360... 

Fig. 8.17. Reprinted with permission of John Wiley Sons, Inc. 1998 from Juan G, et al. (1998). Histone H3 phosphorylation and expression of cyclins A and B1 measured in individual cells during their progression through G2 and mitosis. Cytometry 32 71-77.

Following the S phase is the G2 phase, in which the cell prepares for mitosis and cytokinesis. Although few of the molecular events that occur in G2 phase have been identified, it is known that some proteins synthesized during this period are essential for cell division. It is believed that contractile proteins necessary for chromosome separation and cytokinesis accumulate and are accompanied by modifications in the structure of chromosomal proteins. The phosphorylation of histone HI, known to be involved in the packaging of nucleosomes, could cause the initiation of chromosome condensation that directs the cell into mitosis. 

Sarg B, Helliger W, Talasz H, Forg B, Lindner HH. Histone HI phosphorylation occurs site-specifically during interphase and mitosis identification of a novel phosphorylation site on histone HI./Bio/ Chem 2006 281 6573-80. 

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