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@PHDTHESIS{HnleKreidler:286019,
      author       = {S. Hänle-Kreidler$^*$},
      title        = {{C}haracterization of novel substrates of {SCF}-{FBXW}7 in
                      mitotic cell fate regulation},
      volume       = {--},
      school       = {Universität Heidelberg},
      type         = {Dissertation},
      address      = {Heidelberg},
      publisher    = {---},
      reportid     = {DKFZ-2023-02596},
      isbn         = {not applicable},
      series       = {Dissertation},
      pages        = {138},
      year         = {2023},
      note         = {not applicable; Dissertation, Universität Heidelberg,
                      2023},
      abstract     = {Protein ubiquitylation is a post-translational
                      modification, which can control various cellular processes.
                      Ubiquitin is conjugated to a substrate by an enzymatic
                      cascade comprising so-called ubiquitin writers: E1, E2 and
                      E3 enzymes. More of the ubiquitin-code is continuously
                      uncovered and functional relationships are established. The
                      induction of proteasomal degradation is probably the most
                      prominent function of protein ubiquitylation. The E3
                      ubiquitin ligases convey specificity by facilitating the
                      substrate interaction. SKP1-CUL1-F-box protein complexes
                      belong to the RING E3 ubiquitin ligases and are one of the
                      largest groups of the over 600 human E3 ubiquitin ligases.
                      Their substrate receptors, the F-box proteins, are
                      interchangeable and they can therefore target a vast number
                      of substrates. FBXW7 is one of the best characterized F-box
                      proteins and acts as a tumor suppressor by targeting
                      oncogenes like c-Myc, Cyclin E1 and NOTCH1 for degradation.
                      Being the most frequently mutated F-box protein in human
                      cancers, FBXW7 loss-of-function or deletion result in
                      increased tumor proliferation and chemoresistance.
                      FBXW7-deficiency promotes mitotic slippage in response to
                      antimicrotubule drugs and the identification of FBXW7
                      substrates responsible for this phenotype remains a major
                      task.In the presented thesis, I aimed at identifying novel
                      substrates of FBXW7 which are involved in mitotic slippage
                      to better understand mitotic cell fate regulation. Using a
                      proteomics approach, I identified the Histone 3 lysine 4
                      methyltransferase complex component WDR5 as FBXW7 candidate
                      substrates and showed that FBXW7 regulates WDR5 protein
                      levels by ubiquitylation. I verified that FBXW7 and WDR5
                      interact in-vivo and in-vitro and found that the
                      overexpression of WDR5 and Cyclin E1 can promote mitotic
                      slippage. Reciprocally, the depletion of WDR5 and Cyclin E1
                      reduced mitotic slippage induced by knockdown of FBXW7 and
                      significantly reduced polyploidization after mitotic
                      slippage. Although the methyltransferase enzymatic subunit
                      KMT2D is a substrate of FBXW7 and cooperates with WDR5,
                      knockdown of KMT2D did not affect mitotic cell
                      fate.Collectively, I identified WDR5 as a novel substrate of
                      FBXW7 and showed that the FBXW7 substrates WDR5 and Cyclin
                      E1 can promote mitotic slippage and are required for
                      drug-induced polyploidy. My results help to better
                      understand the mechanisms underlying chemotherapy resistance
                      caused by treatment of cancers with antimicrotubule drugs.},
      cin          = {F045},
      cid          = {I:(DE-He78)F045-20160331},
      pnm          = {316 - Infektionen, Entzündung und Krebs (POF4-316)},
      pid          = {G:(DE-HGF)POF4-316},
      typ          = {PUB:(DE-HGF)3 / PUB:(DE-HGF)11},
      urn          = {---},
      url          = {https://inrepo02.dkfz.de/record/286019},
}