<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "The regulation of polo-like kinase 4 in centrosome duplication"^^ . "Centrosomes are important cell organelles that serve as main microtubule-organizing\r\ncenters and are involved in diverse cellular processes, most importantly cell division\r\nby facilitating formation of the bipolar spindle in mitosis. Each centrosome consists of\r\na pair of centrioles, which is duplicated exactly once per cell cycle. The\r\nserine/threonine protein kinase polo-like kinase 4, PLK4, is known as the master\r\nregulator of centriole duplication. Overexpression of PLK4 is sufficient to induce tumor\r\nformation in mice, by causing centrosome amplification and chromosome\r\nmissegregation in mitosis as a source for genomic instability. In order to prevent\r\ncentriole overduplication, PLK4 protein levels are tightly regulated by ubiquitylation and\r\nproteasomal degradation. Protein ubiquitylation is a post-translational modification,\r\ncarried out by an enzymatic cascade consisting of three enzymes: E1, E2 and E3. The\r\nSKP1-CUL1-b-TrCP E3 ubiquitin ligase complex has been shown to recognize the\r\nsubstrate PLK4 upon trans-autophosphorylation of a degron motif and regulate its\r\nprotein levels by ubiquitylation and proteasomal degradation. However, a b-TrCP\r\nbinding mutant of PLK4 has been found to be still ubiquitylated and partly degraded,\r\nindicating that the exact regulation of PLK4 protein levels has not been unraveled\r\nentirely yet.\r\nIn the presented thesis, I identified PLK4 as a novel substrate of the E3 ubiquitin ligase\r\nCUL4-DDB1-DCAF1, CRL4DCAF1, which ubiquitylates and thereby targets PLK4 for\r\ndegradation in G2 phase of the cell cycle to prevent premature centriole duplication in\r\nmitosis. DCAF1 serves as a substrate binding domain of the complex, which I showed\r\nto bind PLK4 in a phosphorylation-independent manner. Overexpression of DCAF1\r\nenhanced the ubiquitylation of PLK4, while knockdown of DCAF1 increased PLK4\r\nprotein levels and caused the formation of multipolar spindles in mitosis. I found that\r\nthe regulation of PLK4 by CRL4DCAF1 also affects the interaction between PLK4 and its\r\nsubstrate STIL, as well as the process of centriole disengagement at the onset of\r\ncentriole biogenesis. Taken together, I identified a new mechanism for regulating PLK4\r\nprotein levels in centriole duplication that is dependent on the CRL4DCAF1 ubiquitin\r\nligase complex. My results contribute to a better understanding of the complex\r\nregulation and might open up new possibilities to target deregulated or overexpressed\r\nPLK4 as a novel approach for cancer therapy."^^ . "2024" . . . . . . . "Josina"^^ . "Großmann"^^ . "Josina Großmann"^^ . . . . . . "The regulation of polo-like kinase 4 in centrosome duplication (PDF)"^^ . . . "PhD thesis Josina Großmann 2024.pdf"^^ . . . "The regulation of polo-like kinase 4 in centrosome duplication (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "The regulation of polo-like kinase 4 in centrosome duplication (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "The regulation of polo-like kinase 4 in centrosome duplication (Other)"^^ . . . . . . "preview.jpg"^^ . . . "The regulation of polo-like kinase 4 in centrosome duplication (Other)"^^ . . . . . . "medium.jpg"^^ . . . "The regulation of polo-like kinase 4 in centrosome duplication (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #34989 \n\nThe regulation of polo-like kinase 4 in centrosome duplication\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .