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Title: Characterization of the role of the Aurora B kinase in quiescent lymphocytes
Author: Frangini, Alberto
ISNI:       0000 0004 2741 7316
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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The role of the Aurora B kinase in mediating cellular functions outside mitosis was investigated. A SILAC-based approach was used to show that Aurora B interacts with proteins implicated in gene regulation and chromatin organization in G1 activated B cells. Among these interactors, I identified the PRC1 component Ring1B as a new partner of Aurora B. Both proteins are bound to the promoters of highly expressed genes in resting B and T lymphocytes. Quiescent resting B cells require the maintenance of a transcriptional programme that keeps the cells viable and ready to proliferate upon encounter with a specific antigen. Aurora B and Ring1B physically co-occupy the same promoters in resting B cells but, upon activation, Aurora B is replaced by MSK1 on its target genes, whereas Ring1B binding is preserved. Analysis of the active promoters in resting B cells shows that other PRC1 components, such as Cbx7 and Bmi1, and the histone deubiquitinase USP16, together with Aurora B and Ring1B, bind almost exclusively to the regulatory elements of active promoters and are not found at repressed genes. Binding of PRC2 components and deposition of the H3K27me3 and H2Aubq marks are largely confined to silent genes. By employing conditional knockout mouse models, I showed that removal of either Aurora B or Ring1B results in a global reduction in the binding of unphosphorylated and serine 5-phosphorylated RNA Polymerase II to active promoters. This phenomenon is also accompanied by a reduction in the production of transcripts from Aurora B and Ring1B target genes and reduced cell viability. Aurora B is also required to maintain high levels of phosphorylated H3S28 and low levels of the repressive H2Aubq mark at active promoters. These results identify a new role for both Aurora B and Ring1B in the regulation of active transcription in quiescent lymphocytes.
Supervisor: Dillon, Niall ; Sabbattini, Pierangela Sponsor: Leukaemia & Lymphoma Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral