Variations in Prkdc encoding the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and susceptibility to radiation-induced apoptosis and lymphomagenesis
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)F(1) x 129/SvJ and (C.S-R1 x BALB/c)F(1) 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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Balb/c mice have 2 different polymorphisms in DNA-dependent protein kinase (DNA-PKcs) that mediates non-homologous end joining, which results in decreased but not absent function.
“Balb/c mice have 2 different polymorphisms in DNA-dependent protein kinase (DNA-PKcs) that mediates non-homologous end joining, which results in decreased but not absent function [42], [43], [44].”
From Hindlimb suspension and spe-like radiation impairs clearance of bacterial infections (2014) · cites this paper as [43]
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- Authors
- Mori, N., Matsumoto, Y., Okumoto, M., Suzuki, N., & Yamate, J.
- Affiliations
- The University of Tokyo (JP)
- Osaka Prefecture University (JP)
- Venue
- Oncogene
- Published
- 2001-06-21
- Volume
- 20
- Issue
- 28
- Pages
- 3609-3619
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2330684871
- Cited by
- 63
- References
- 39
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 5 · 2014: 3 · 2013: 3 · 2012: 1
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Tokyo Tech Research Repository (Tokyo Institute of Technology) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- PRKDC, DNA-PKcs, radiation-induced apoptosis, radiation susceptibility, DNA double-strand break repair, congenic strains, BALB/c mice, amino acid substitutions, leucine zipper, kinase domain, inbred mouse strains
- MeSH terms
- Alleles, Animals, Cell Transformation, Neoplastic, Chromosome Mapping, DNA-Binding Proteins, Female, Lymphoma, Mice, Inbred BALB C, Mice, Inbred C57BL, Nuclear Proteins, Radiation Tolerance, Recombination, Genetic, Genetic Variation, Apoptosis, Protein Serine-Threonine Kinases, Genetic Predisposition to Disease, Catalytic Domain, Mice, DNA-Activated Protein Kinase
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