Regulation of Mitotic Chromosome Cohesion by Haspin and Aurora B

Abstract

In vertebrate mitosis, cohesion between sister chromatids is lost in two stages. In prophase and prometaphase, cohesin release from chromosome arms occurs under the control of Polo-like kinase 1 and Aurora B, while Shugoshin is thought to prevent removal of centromeric cohesin until anaphase. The regulatory enzymes that act to sustain centromeric cohesion are incompletely described, however. Haspin/Gsg2 is a histone H3 threonine-3 kinase required for normal mitosis. We report here that both H3 threonine-3 phosphorylation and cohesin are located at inner centromeres. Haspin depletion disrupts cohesin binding and sister chromatid association in mitosis, preventing normal chromosome alignment and activating the spindle assembly checkpoint, leading to arrest in a prometaphase-like state. Overexpression of Haspin hinders cohesin release and stabilizes arm cohesion. We conclude that Haspin is required to maintain centromeric cohesion during mitosis. We also suggest that Aurora B regulates cohesin removal through its effect on the localization of Shugoshin.

The MUT9p kinase phosphorylates histone H3 threonine 3 and is necessary for heritable epigenetic silencing in Chlamydomonas

“…In several plant species, similarly to metazoans, histone H3 is hyperphosphorylated at Ser-10/28 during mitosis and meiosis, and these modifications appear to be required for proper chromosome segregation and cell cycle progression (9,10,11). H3S10 phosphorylation (H3S10ph) is also involved in the transcriptional activation of genes responding to stress or mitogenstimulated signaling pathways in animals (10,12), and it has been found to increase transiently in plant cells subject to abiotic stresses (9,13).…”

The Mitotic Protein Kinase Haspin and Its Inhibitors

“…It was subsequently renamed haploid germ cell-specific nuclear protein kinase (Haspin) [4]. Haspin mRNA is found in diploid cells of many proliferative tissues such as testis, thymus, bone marrow, and spleen as well as in many proliferative cell lines [5][6][7]. Its expression is comparatively reduced in somatic tissues.…”

“…Prometaphase and metaphase duration are increased due to severe chromosome alignment defects [6,7,13] (Figure 4). Mitosis duration, measured by video microscopy, is increased up to several hours in Haspindepleted U-2 OS cells [36].…”

“…The phosphorylation decreases rapidly at anaphase and can still be observed on telomeres present in the vicinity of Aurora B activity area on the midzone. It is no longer detected on chromosomes, when cells are in late telophase ( Figure 5 upper panel) [6,7,13,14].…”

“…Defects in chromosome alignment in Haspin-depleted cells are probably due, at least in part, to a premature loss of sister chromatid cohesion [6].…”