Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice

Yangbo Yue, Stanley G. Leung, Yueyong Liu, Yurong Huang, Kirsten Grundt, Anne Carine Østvold, Kuang-Yu Jen, David Schild, Jian Hua Mao, Claudia Wiese

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

NUCKS1 is a 27 kD vertebrate-specific protein, with a role in the DNA damage response. Here, we show that after 4 Gy total-body X-irradiation, Trp53+/- Nucks1+/- mice more rapidly developed tumors, particularly thymic lymphoma (TL), than Trp53+/- mice. TLs in both cohorts showed loss of heterozygosity (LOH) of the Trp53+ allele in essentially all cases. In contrast, LOH of the Nucks1+ allele was rare. Nucks1 expression correlated well with Nucks1 gene dosage in normal thymi, but was increased in the majority of TLs from Trp53+/- Nucks1+/- mice, suggesting that elevated Nucks1 message may be associated with progression towards malignancy in vivo. Trp53+/- Nucks1+/- mice frequently succumbed to CD4- CD8- TLs harboring translocations involving Igh but not Tcra/d, indicating TLs in Trp53+/- Nucks1+/- mice mostly originated prior to the double positive stage and at earlier lineage than TLs in Trp53+/- mice. Monoclonal rearrangements at Tcrb were more prevalent in TLs from Trp53+/- Nucks1+/- mice, as was infiltration of primary TL cells to distant organs (liver, kidney and spleen). We propose that, in the context of Trp53 deficiency, wild type levels of Nucks1 are required to suppress radiation-induced TL, likely through the role of the NUCKS1 protein in the DNA damage response.

Original languageEnglish (US)
Pages (from-to)61874-61889
Number of pages16
JournalOncotarget
Volume7
Issue number38
DOIs
StatePublished - Jan 1 2016

Keywords

  • Double-strand break repair
  • Ionizing radiation
  • NUCKS1
  • Thymic lymphoma
  • V(D)J recombination

ASJC Scopus subject areas

  • Oncology

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    Yue, Y., Leung, S. G., Liu, Y., Huang, Y., Grundt, K., Østvold, A. C., Jen, K-Y., Schild, D., Mao, J. H., & Wiese, C. (2016). Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice. Oncotarget, 7(38), 61874-61889. https://doi.org/10.18632/oncotarget.11297