Regulation of dynein localization and ciliogenesis by ASUNDER via its role in the RNA processing complex, Integrator
Jodoin, Jeanne Nicole
Cytoplasmic dynein is a large, multimeric complex that walks along microtubules to perform multiple functions within the cell. This motor is commonly found associated with the dynein-activating complex, dynactin. Dynein is required for a variety of essential functions such as cargo transport, organelle positioning, centrosome assembly and coupling to the nuclear envelope at the G2/M transition, mitotic spindle positioning, and ciliogenesis. Due to the vast number of roles within the cell, dynein complexes are subject to multiple layers of regulation, including binding of accessory proteins, phosphorylation, variations in subunit composition, and subcellular localization. Additionally, dynein roles are often cell cycle dependent. At the G2/M transition, a subpopulation of dynein is found anchored to the nuclear envelope in multiple species. In cultured human cells, this pool facilitates centrosome coupling to the nuclear envelope, centrosome splitting and migration to the presumptive poles, and nuclear envelope breakdown. Bicaudal D2 and Centromere protein F are required for anchoring this pool of dynein on the nuclear envelope. Another cell cycle-dependent role for dynein is primary ciliogenesis during G1 in cultured human cells. Dynein is required for promoting assembly of the primary cilium as well as regulating its length. For both functions, the complete mechanism for regulating dynein remains unclear. Asunder has been previously shown to regulate perinuclear dynein at G2/M in Drosophila spermatogenesis. Additionally, Asunder has been shown to be an essential subunit in the small nuclear RNA-processing complex, Integrator. Herein, I present data showing that Asunder has a conserved role in regulating perinuclear dynein in cultured human cells via its role in the Integrator complex. I additionally report that Integrator is required for primary ciliogenesis in G1-arrested cells. My work supports the model that Integrator independently regulates these cellular events at the RNA-processing level. This works expands our understanding of the mechanisms for dynein anchoring to the nuclear surface at G2/M and ciliogenesis by adding an RNA-processing component.