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  • Original Paper
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Variations in Prkdc encoding the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and susceptibility to radiation-induced apoptosis and lymphomagenesis

Oncogene volume 20, pages 3609–3619 (2001)Cite this article

Abstract

DNA double-strand breaks (DSBs) induced by ionizing radiation enforce cells to die, if unrepaired; while if misrepaired, DSBs may cause malignant transformation. The DSB repair system predominant in mammals requires DNA-dependent protein kinase (DNA-PK). Previously, we identified the apoptosis susceptibility gene Radiation-induced apoptosis 1 (Rapop1) on mouse chromosome 16. The STS/A (STS) allele at Rapop1 leads to decreased sensitivity to apoptosis in the BALB/cHeA (BALB/c) background. In the present study, we established Rapop1 congenic strains C.S-R1 and C.S-R1L, which contain the STS genome in a 0.45 cM interval critical for Rapop1 in common in the BALB/c background. Within the segment critical for Rapop1, Prkdc encoding the catalytic subunit of DNA-PK (DNA-PKcs) was assigned. Two variations T6,418C and G11,530A, which induce amino acid substitutions C2,140R downstream from the putative leucine zipper motif and V3,844M near the kinase domain, respectively, were found between BALB/c and STS for Prkdc. The majority of inbred strains such as C57BL/6J carried the STS allele at Prkdc; a few strains including 129/SvJ and C.B17 carried the BALB/c allele. DNA-PK activity as well as DNA-PKcs expression was profoundly diminished in BALB/c and 129/SvJ mice as compared with C57BL/6 and C.S-R1 mice. In the crosses (C.S-R1 x BALB/c)F1 x 129/SvJ and (C.S-R1 x BALB/c)F1 x C.B17, enhanced apoptosis occurred in the absence of the wild-type allele at Prkdc. C.S-R1 and C.S-R1L were both less sensitive to radiation lymphomagenesis than BALB/c. Our study provides strong evidence for Prkdc as a candidate for Rapop1 and a susceptibility gene for radiation lymphomagenesis as well.

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Acknowledgements

We are grateful to Dr P Demant (The Netherlands Cancer Institute, Amsterdam NL) for his kind gift of recombinant congenic mice. We thank Dr Kominami at Niigata University, Japan, for his helpful discussion during preparation of this paper. We thank Y Ujihara and M Ikeda at the Research Institute for Advanced Science and Technology, Osaka Prefecture University (Osaka, Japan) for their technical assistance in animal care. This study is partly supported by a grant No. 1068521 from the Ministry of Education, Science, Sports and Culture of Japan to N Mori and by a grant from Japan Atomic Energy Research Institute under a contract to the Nuclear Safety Research Association to M Okumoto.

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Authors and Affiliations

  1. Department of Applied Bioscience, Research Institute for Advanced Science and Technology, Osaka, 599-8570, Japan

    Nobuko Mori & Masaaki Okumoto

  2. Department of Veterinary Pathology, College of Agriculture, Osaka Prefecture University, 1-2 Gakuen-cho, Sakai, 599-8570, Osaka, Japan

    Jyoji Yamate

  3. Department of Radiation Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Yoshihisa Matsumoto & Norio Suzuki

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  1. Nobuko Mori
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Correspondence to Nobuko Mori.

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Mori, N., Matsumoto, Y., Okumoto, M. et al. Variations in Prkdc encoding the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and susceptibility to radiation-induced apoptosis and lymphomagenesis. Oncogene 20, 3609–3619 (2001). https://doi.org/10.1038/sj.onc.1204497

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