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

DNA double-strand breaks (DSBs) induced by ionizing radiation enforce cells to die, if unrepaired; while if misrepaired, DSBs may cause malignant tran sformation. The DSB repair system predominant in mammals requires DNA-depen dent protein kinase (DNA-PK), Previously, we identified the apoptosis susce ptibility gene Radiation-induced apoptosis 1 (Rapop1) on mouse chromosome 1 6, The STS/A (STS) allele at Rapop1 leads to decreased sensitivity to apopt osis in the BALB/cHeA (BALB/c) background. In the present study, we establi shed Rapop1 congenic strains C,S-RI and C.S-R1L, which contain the STS geno me in a 0.45 cM interval critical for Rapop1 in common in the BALB/c backgr ound. Within the segment critical for Rapop1, Prkdc encoding the catalytic subunit of DNA-PK (DNA-PKcs) was assigned. Two variations T6,418C and G11,5 30A, which induce amino acid substitutions C2,140R downstream from the puta tive leucine zipper motif and V3,844M near the kinase domain, respectively, were found between BALB/c and STS for Prkdc. The majority of inbred strain s 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 DN A-PKcs expression was profoundly diminished in BALB/c and 129/SvJ mice as c ompared 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 t he absence of the wildtype allele at Prkdc. C.S-R1 and C.S-R1L were both le ss sensitive to radiation lymphomagenesis than BALB/ c, Our study provides strong evidence for Prkdc as a candidate for Rapop1 and a susceptibility ge ne for radiation lymphomagenesis as well.