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To maintain their genetic integrity, eukaryotic cells must segregate their chromosomes properly to opposite spindle poles during mitosis. This process has important medical relevance because chromosome mis-segregation plays causative roles in human diseases such as cancers and congenital diseases. To prepare for proper chromosome segregation, kinetochores – the spindle attachment sites on chromosomes – must correctly interact with spindle microtubules (MTs) during early mitosis.
Self-assembly of larger protein networks is a central feature of replicating systems from viral capsids to the cytoskeleton that gives cells structure and polarity. One important example is the nuclear lamina, a subset of the cytoskeleton responsible for nuclear structural integrity, controlling the demarcation between active and inactive chromatin and the developmental control of gene expression programs.
Arsenic trioxide therapy for Acute Promyelocytic Leukaemia (APL) is mediated by SUMO-dependent degradation of Promyelocytic Leukaemia (PML)-Retinoic Acid Receptor α (RARα) oncogenic fusion protein. We demonstrated (Tatham et al., 2008) that ubiquitin mediated proteolysis of PML requires RNF4 E3 ubiquitin ligase. This allows terminal differentiation of tumour cells and cures disease. The primary effect of arsenic is to dramatically increase the SUMO modification of the PML protein, however the mechanistic basis for remarkable observation remains unclear.