title: Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice.
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.
authors.affiliation: Department of Organismal Systems and Bioresilience, Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.|Present address: Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Yue
authors.affiliation: Department of Organismal Systems and Bioresilience, Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Leung
authors.affiliation: Department of Organismal Systems and Bioresilience, Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Yueyong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Organismal Systems and Bioresilience, Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Science, University of Oslo, 0317 Oslo, Norway.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Grundt
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Science, University of Oslo, 0317 Oslo, Norway.
authors.forename: Anne-Carine
authors.initials: AC
authors.lastname: Østvold
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Davis, CA 95817, USA.
authors.forename: Kuang-Yu
authors.initials: KY
authors.lastname: Jen
authors.affiliation: Department of Organismal Systems and Bioresilience, Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schild
authors.affiliation: Department of Organismal Systems and Bioresilience, Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.affiliation: Department of Organismal Systems and Bioresilience, Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.|Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wiese
mesh_terms: D000483:Alleles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D055028:Comparative Genomic Hybridization; D004249:DNA Damage; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D057895:Haploinsufficiency; D016130:Immunophenotyping; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D019656:Loss of Heterozygosity; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016159:Tumor Suppressor Protein p53; C000591522:Nucks1 protein, mouse
keywords: NUCKS1; V(D)J recombination; double-strand break repair; ionizing radiation; thymic lymphoma