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@PHDTHESIS{Gromann:294711,
      author       = {J. Großmann$^*$},
      title        = {{T}he regulation of polo-like kinase 4 in centrosome
                      duplication},
      school       = {Universität Heidelberg},
      type         = {Dissertation},
      publisher    = {Heidelberg University Library},
      reportid     = {DKFZ-2024-02444},
      year         = {2024},
      note         = {Dissertation, Universität Heidelberg, 2024},
      abstract     = {Centrosomes are important cell organelles that serve as
                      main microtubule-organizing centers and are involved in
                      diverse cellular processes, most importantly cell division
                      by facilitating formation of the bipolar spindle in mitosis.
                      Each centrosome consists of a pair of centrioles, which is
                      duplicated exactly once per cell cycle. The serine/threonine
                      protein kinase polo-like kinase 4, PLK4, is known as the
                      master regulator of centriole duplication. Overexpression of
                      PLK4 is sufficient to induce tumor formation in mice, by
                      causing centrosome amplification and chromosome
                      missegregation in mitosis as a source for genomic
                      instability. In order to prevent centriole overduplication,
                      PLK4 protein levels are tightly regulated by ubiquitylation
                      and proteasomal degradation. Protein ubiquitylation is a
                      post-translational modification, carried out by an enzymatic
                      cascade consisting of three enzymes: E1, E2 and E3. The
                      SKP1-CUL1-b-TrCP E3 ubiquitin ligase complex has been shown
                      to recognize the substrate PLK4 upon
                      trans-autophosphorylation of a degron motif and regulate its
                      protein levels by ubiquitylation and proteasomal
                      degradation. However, a b-TrCP binding mutant of PLK4 has
                      been found to be still ubiquitylated and partly degraded,
                      indicating that the exact regulation of PLK4 protein levels
                      has not been unraveled entirely yet. In the presented
                      thesis, I identified PLK4 as a novel substrate of the E3
                      ubiquitin ligase CUL4-DDB1-DCAF1, CRL4DCAF1, which
                      ubiquitylates and thereby targets PLK4 for degradation in G2
                      phase of the cell cycle to prevent premature centriole
                      duplication in mitosis. DCAF1 serves as a substrate binding
                      domain of the complex, which I showed to bind PLK4 in a
                      phosphorylation-independent manner. Overexpression of DCAF1
                      enhanced the ubiquitylation of PLK4, while knockdown of
                      DCAF1 increased PLK4 protein levels and caused the formation
                      of multipolar spindles in mitosis. I found that the
                      regulation of PLK4 by CRL4DCAF1 also affects the interaction
                      between PLK4 and its substrate STIL, as well as the process
                      of centriole disengagement at the onset of centriole
                      biogenesis. Taken together, I identified a new mechanism for
                      regulating PLK4 protein levels in centriole duplication that
                      is dependent on the CRL4DCAF1 ubiquitin ligase complex. My
                      results contribute to a better understanding of the complex
                      regulation and might open up new possibilities to target
                      deregulated or overexpressed PLK4 as a novel approach for
                      cancer therapy.},
      keywords     = {570 Life sciences (Other)},
      cin          = {D345},
      cid          = {I:(DE-He78)D345-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.11588/HEIDOK.00034989},
      url          = {https://inrepo02.dkfz.de/record/294711},
}