MITOTIC REGULATION OF NUCLEAR ASSEMBLY, POSITIONING AND FUNCTION

The eukaryotic nucleus is assembled, disassembled and positioned in a regulated fashion through mitotic progression. During mitotic entry, an interplay between kinases including the cyclin dependent kinase 1 (CDK1) with its binding partner Cyclin B (CycB), CDK1-CybB, and phosphatases including protein phosphatase 2A (PP2A) with its mitotic adapter subunit B55 (PP2A-B55) regulate the timely cascade of mitotic events, as well as the irreversibility and directionality of these events. Here, PP2A-B55-driven signaling is shown to collaborate with nucleo-cytoplasmic trafficking (NCT) and the nuclear lamina in modulating two mechanical components of the mitotic nucleus. First, nuclear expansion during mitotic exit is shown to occur in a volume-dependent manner, requiring proper NCT. Second, nuclear expansion and size regulation are shown to be critical for centrosome separation during mitotic entry through the regulation of Dynein density on the pronuclear envelope the in C. elegans zygote. Together, these mechanisms provide insight into the mitotic regulation of nuclear mechanics critical to mitotic progression. Gaining insight into the biology of the nucleus is likely to shed light on developmental and disease states such as aging and cancer in which nuclear size and shape are perturbed.Doctor of Philosoph