@article{GhanawiHennleinZareetal.2021,
  author    = {Ghanawi, Hanaa and Hennlein, Luisa and Zare, Abdolhossein and Bader, Jakob and Salehi, Saeede and Hornburg, Daniel and Ji, Changhe and Sivadasan, Rajeeve and Drepper, Carsten and Meissner, Felix and Mann, Matthias and Jablonka, Sibylle and Briese, Michael and Sendtner, Michael},
  title     = {Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin},
  series = {Nucleic Acids Research},
  volume    = {49},
  journal   = {Nucleic Acids Research},
  number    = {21},
  doi       = {10.1093/nar/gkab1120},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265687},
  pages     = {12284-12305},
  year      = {2021},
  abstract  = {Neurons critically rely on the functions of RNA-binding proteins to maintain their polarity and resistance to neurotoxic stress. HnRNP R has a diverse range of post-transcriptional regulatory functions and is important for neuronal development by regulating axon growth. Hnrnpr pre-mRNA undergoes alternative splicing giving rise to a full-length protein and a shorter isoform lacking its N-terminal acidic domain. To investigate functions selectively associated with the full-length hnRNP R isoform, we generated a Hnrnpr knockout mouse (Hnrnpr\(^{tm1a/tm1a}\)) in which expression of full-length hnRNP R was abolished while production of the truncated hnRNP R isoform was retained. Motoneurons cultured from Hnrnpr\(^{tm1a/tm1a}\) mice did not show any axonal growth defects but exhibited enhanced accumulation of double-strand breaks and an impaired DNA damage response upon exposure to genotoxic agents. Proteomic analysis of the hnRNP R interactome revealed the multifunctional protein Yb1 as a top interactor. Yb1-depleted motoneurons were defective in DNA damage repair. We show that Yb1 is recruited to chromatin upon DNA damage where it interacts with gamma-H2AX, a mechanism that is dependent on full-length hnRNP R. Our findings thus suggest a novel role of hnRNP R in maintaining genomic integrity and highlight the function of its N-terminal acidic domain in this context.},
  language  = {en}
}
@article{KunzBommertKruketal.2020,
  author    = {Kunz, Viktoria and Bommert, Kathryn S. and Kruk, Jessica and Schwinning, Daniel and Chatterjee, Manik and St{\"u}hmer, Thorsten and Bargou, Ralf and Bommert, Kurt},
  title     = {Targeting of the E3 ubiquitin-protein ligase HUWE1 impairs DNA repair capacity and tumor growth in preclinical multiple myeloma models},
  series = {Scientific Reports},
  volume    = {10},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-020-75499-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230632},
  year      = {2020},
  abstract  = {Experimental evidence suggests that ubiquitin-protein ligases regulate a number of cellular processes involved in tumorigenesis. We analysed the role of the E3 ubiquitin-protein ligase HUWE1 for pathobiology of multiple myeloma (MM), a still incurable blood cancer. mRNA expression analysis indicates an increase in HUWE1 expression levels correlated with advanced stages of myeloma. Pharmacologic as well as RNAi-mediated HUWE1 inhibition caused anti-proliferative effects in MM cell lines in vitro and in an MM1.S xenotransplantation mouse model. Cell cycle analysis upon HUWE1 inhibition revealed decreased S phase cell fractions. Analyses of potential HUWE1-dependent molecular functions did not show involvement in MYC-dependent gene regulation. However, HUWE1 depleted MM cells displayed increased DNA tail length by comet assay, as well as changes in the levels of DNA damage response mediators such as pBRCA1, DNA-polymerase beta, gamma H2AX and Mcl-1. Our finding that HUWE1 might thus be involved in endogenous DNA repair is further supported by strongly enhanced apoptotic effects of the DNA-damaging agent melphalan in HUWE1 depleted cells in vitro and in vivo. These data suggest that HUWE1 might contribute to tumour growth by endogenous repair of DNA, and could therefore potentially be exploitable in future treatment developments.},
  language  = {en}
}