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Title: Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice

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:
 [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [2] ;  [3] ;  [1] ;  [1] ;  [4]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Department of Organismal Systems and Bioresilience, Biological Systems and Engineering Division
  2. Univ. of Oslo (Norway). Department of Molecular Medicine, Institute of Basic Medical Science
  3. Univ. of California, Davis, CA (United States). Department of Pathology and Laboratory Medicine
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Department of Organismal Systems and Bioresilience, Biological Systems and Engineering Division; Colorado State Univ., Fort Collins, CO (United States). Department of Environmental and Radiological Health Sciences
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Accepted Manuscript
Journal Name:
Oncotarget
Additional Journal Information:
Journal Volume: 7; Journal Issue: 38; Journal ID: ISSN 1949-2553
Publisher:
Impact Journals
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; NUCKS1; double-strand break repair; ionizing radiation; thymic lymphoma; V(D)J recombination
OSTI Identifier:
1378756

Yue, Yangbo, Leung, Stanley G., Liu, Yueyong, Huang, Yurong, Grundt, Kirsten, Østvold, Anne-Carine, Jen, Kuang-Yu, Schild, David, Mao, Jian-Hua, and Wiese, Claudia. Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice. United States: N. p., Web. doi:10.18632/oncotarget.11297.
Yue, Yangbo, Leung, Stanley G., Liu, Yueyong, Huang, Yurong, Grundt, Kirsten, Østvold, Anne-Carine, Jen, Kuang-Yu, Schild, David, Mao, Jian-Hua, & Wiese, Claudia. Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice. United States. doi:10.18632/oncotarget.11297.
Yue, Yangbo, Leung, Stanley G., Liu, Yueyong, Huang, Yurong, Grundt, Kirsten, Østvold, Anne-Carine, Jen, Kuang-Yu, Schild, David, Mao, Jian-Hua, and Wiese, Claudia. 2016. "Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice". United States. doi:10.18632/oncotarget.11297. https://www.osti.gov/servlets/purl/1378756.
@article{osti_1378756,
title = {Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice},
author = {Yue, Yangbo and Leung, Stanley G. and Liu, Yueyong and Huang, Yurong and Grundt, Kirsten and Østvold, Anne-Carine and Jen, Kuang-Yu and Schild, David and Mao, Jian-Hua and Wiese, Claudia},
abstractNote = {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.},
doi = {10.18632/oncotarget.11297},
journal = {Oncotarget},
number = 38,
volume = 7,
place = {United States},
year = {2016},
month = {8}
}