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

Oncogene. 2001 Jun 21;20(28):3609-19. doi: 10.1038/sj.onc.1204497.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Apoptosis / genetics*
  • Catalytic Domain
  • Cell Transformation, Neoplastic / genetics
  • Chromosome Mapping
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Lymphoma / genetics*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Nuclear Proteins
  • Protein-Serine-Threonine Kinases / genetics*
  • Radiation Tolerance / genetics
  • Recombination, Genetic

Substances

  • DNA-Binding Proteins
  • Nuclear Proteins
  • DNA-Activated Protein Kinase
  • Prkdc protein, mouse
  • Protein-Serine-Threonine Kinases