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Yan, Catherine

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Yan

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Catherine

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Yan, Catherine

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2008 - 200912010 - 20171

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Author's Publications: search.filters.isAuthorOfPublication.601ff1f3-83cf-4f89-9a03-16e84b88298b

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    Contribution of classical end-joining to PTEN inactivation in p53-mediated glioblastoma formation and drug-resistant survival
    (Nature Publishing Group, 2017) Kang, Youn-Jung; Balter, Barbara; Csizmadia, Eva; Haas, Brian; Sharma, Himanshu; Bronson, Roderick; Yan, Catherine
    DNA repair gene defects are found in virtually all human glioblastomas, but the genetic evidence for a direct role remains lacking. Here we demonstrate that combined inactivation of the XRCC4 non-homologous end-joining (NHEJ) DNA repair gene and p53 efficiently induces brain tumours with hallmark characteristics of human proneural/classical glioblastoma. The murine tumours exhibit PTEN loss of function instigated by reduced PTEN mRNA, and increased phosphorylated inactivation and stability as a consequence of aberrantly elevated CK2 provoked by p53 ablation and irrevocably deregulated by NHEJ inactivation. This results in DNA damage-resistant cytoplasmic PTEN and CK2 expression, and the attenuation of DNA repair genes. CK2 inhibition restores PTEN nuclear distribution and DNA repair activities and impairs tumour but not normal cell survival. These observations demonstrate that NHEJ contributes to p53-mediated glioblastoma suppression, and reveal a crucial role for PTEN in the early DNA damage signalling cascade, the inhibition of which promotes tumorigenicity and drug-resistant survival.
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    Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching
    (The Rockefeller University Press, 2008) Wang, Jing; Alt, Frederick; Gostissa, Monica; Datta, Abhishek; Murphy, Michael; Alimzhanov, Marat B.; Coakley, Kristen M.; Rajewsky, Klaus; Manis, John; Yan, Catherine
    Nonhomologous end-joining (NHEJ) repairs DNA double-strand breaks (DSBs) during V(D)J recombination in developing lymphocytes and during immunoglobulin (Ig) heavy chain (IgH) class switch recombination (CSR) in peripheral B lymphocytes. We now show that CD21-cre–mediated deletion of the Xrcc4 NHEJ gene in p53-deficient peripheral B cells leads to recurrent surface Ig-negative B lymphomas (“CXP lymphomas”). Remarkably, CXP lymphomas arise from peripheral B cells that had attempted both receptor editing (secondary V[D]J recombination of Igκ and Igλ light chain genes) and IgH CSR subsequent to Xrcc4 deletion. Correspondingly, CXP tumors frequently harbored a CSR-based reciprocal chromosomal translocation that fused IgH to c-myc, as well as large chromosomal deletions or translocations involving Igκ or Igλ, with the latter fusing Igλ to oncogenes or to IgH. Our findings reveal peripheral B cells that have undergone both editing and CSR and show them to be common progenitors of CXP tumors. Our studies also reveal developmental stage-specific mechanisms of c-myc activation via IgH locus translocations. Thus, Xrcc4/p53-deficient pro–B lymphomas routinely activate c-myc by gene amplification, whereas Xrcc4/p53-deficient peripheral B cell lymphomas routinely ectopically activate a single c-myc copy.