|dc.description||Material removed from thesis due to copyright reasons:
Figure 1.1. The hierarchy of chromatin folding. From Felsenfeld, G., & Groudine, M. (2003). Controlling the double helix. Nature, 421(6921), 448-453.
Figure 1.2. The structure of the nucleosome core. From Luger, K., Mäder, A. W., Richmond, R. K., Sargent, D. F., & Richmond, T. J. (1997). Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature,
Figure 1.3. The chromatosome. Figure retrieved from https://mbi-figure.storage.googleapis.com/figure/1389942837319.jpg.
Figure 1.4. Sequence alignment of the somatic main H1 subtypes. Adapted from Hergeth, S. P., & Schneider, R. (2015). The H1 linker histones: Multifunctional proteins beyond the nucleosomal core particle. EMBO Reports, 16(11), 1439-1453.
Figure 1.6. The mechanism of HP1 dislodgement from H1.4. Adapted from Fischle, W., Tseng, B. S., Dormann, H. L., Ueberheide, B. M., Garcia, B. A., Shabanowitz, J., Hunt, D. F., Funabiki, H., & Allis, C. D. (2005). Regulation of HP1–chromatin binding by histone H3 methylation and phosphorylation. Nature, 438(7071), 1116-1122. doi:10.1038/nature04219
Figure 4.1. Comparing H1.4S27 phosphorylation and the mutations that prevent or mimic this phosphorylation. Adapted from Anthis, N. J., Haling, J. R., Oxley, C. L., Memo, M., Wegener, K. L., Lim, C. J., Ginsberg, M. H., & Campbell, I. D. (2009). ß integrin tyrosine phosphorylation is a conserved mechanism for regulating talin-induced integrin activation. Journal of Biological Chemistry, 284(52), 36700-36710. doi: 10.1074/jbc.M109.061275||en_US
|dc.description.abstract||Histone H1 phosphorylation is important for the regulation of high order chromosome
organisation during mitosis. One of these phosphorylation sites in the linker histone
subtype H1.4 is shown here to be phosphorylated by Aurora B kinase, a master
regulator of mitosis. Altered phosphorylation of H1.4 on this phosphorylation site at
serine 27 illustrated the significance of the timing of this phosphorylation. When serine
27 of H1.4 is mutated to prevent this phosphorylation chromosome congression to the
equatorial plate during metaphase is hindered. In contrast, in the presence of the
constitutive H1.4 serine 27 phosphorylation mimic, bridging and lagging chromosomes
occurred, leading to a corresponding increase in the proportion of cells with a
micronucleus. These phenotypes could be brought about through disruption of the
Heterochromatin protein 1 family members bound to the adjacent methylated lysine.
Such aberrations during mitosis can lead to genetic instability and ultimately
aneuploidy, a hallmark of cancer. With the frequently reported over-expression of
Aurora B in cancer this shows another mechanism in which this kinase, via histone
H1.4 phosphorylation, can push a cell toward malignancy.
Another important mitotic kinase, Cyclin dependent kinase 1 together with cyclin B, is
responsible for the hyperphosphorylation of histone H1.4 during mitosis; which is
required for condensing the cells genetic information into highly compact metaphase
chromosomes. This vital mitotic event ensures the faithful transmission of the
duplicated DNA into the dividing daughter cells. The mechanisms through which
histone H1 hyperphosphorylation contribute to chromosome condensation are poorly
understood. One mechanism through which this may occur is via the recruitment of
condensation factors such as the condensins or Topoisomerase II. Here the interaction
between the Condensin I subunit, CAPD2, and histone H1.4 is explored. CAPD2
interacts with the two most prominent linker histone subtypes, H1.4 and H1.2, through
their C-terminal tails. H1.4 and CAPD2 can interact in vitro whilst each is
phosphorylated by cyclin dependent kinase as they are during mitosis, in a manner
dependent on RNA.
Overall, these results indicate that histone H1.4 is a vital component of higher order
chromatin and its phosphorylation is essential for the normal progression through