Research Papers:

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 _ and Claudia Wiese

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Oncotarget. 2016; 7:61874-61889. https://doi.org/10.18632/oncotarget.11297

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Yangbo Yue1,5, Stanley G. Leung1, Yueyong Liu1, Yurong Huang1, Kirsten Grundt2, Anne-Carine Østvold2, Kuang-Yu Jen3, David Schild1, Jian-Hua Mao1, Claudia Wiese1,4

1Department of Organismal Systems and Bioresilience, Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

2Department of Molecular Medicine, Institute of Basic Medical Science, University of Oslo, 0317 Oslo, Norway

3Department of Pathology and Laboratory Medicine, University of California, Davis, CA 95817, USA

4Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA

5Present address: Department of Dermatology, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA

Correspondence to:

Jian-Hua Mao, email: [email protected]

Claudia Wiese, email: [email protected]

Keywords: NUCKS1, double-strand break repair, ionizing radiation, thymic lymphoma, V(D)J recombination

Received: June 20, 2016    Accepted: August 01, 2016    Published: August 16, 2016


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.

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