Abstract
Exposure of cells to ionizing radiation induces DNA double-strand breaks. To repair double-strand breaks correctly, cells must distinguish between the ends of chromosomes (telomeres) and DNA double-strand breaks within chromosomes. Double-strand breaks in telomeric DNA may lead to telomere shortening and mutagenesis. Eukaryotic cells repair double-strand breaks primarily by two mechanisms: error-free homologous recombination and error-prone nonhomologous end joining, of which homologous recombination is used in early meiotic prophase I to create recombined haploid gametes by two meiotic cell divisions lacking an intervening S-phase. Genotoxic exposures put meiosis at risk to transmit mutations, and ionizing radiation is known to induce large double-strand break-marking phospho (gamma)-H2AX foci along the cores and ends of mouse meiotic chromosomes. However, it remained unclear through which repair pathway the ionizing radiation-induced telomeric double-strand breaks are repaired in late prophase I spermatocytes. Using male wild-type and nonhomologous end joining-deficient (severe combined immunodeficient) mice, this study investigated the kinetics of in vivo double-strand break formation and repair at telomeres of late prophase I chromosomes up to 12 h after 0.5 Gy of whole-body gamma irradiation. Late pachytene and diplotene spermatocytes revealed overlapping gamma-H2AX and telomere repeat signal foci, indicating telomeric DNA damage. The comparison of double-strand break repair rates at telomeres and internal prophase chromosome sites revealed a more rapid double-strand break repair at wild-type telomeres during the first hour after irradiation. Increased double-strand break foci numbers at nonhomologous end joining-deficient telomeres and chromosomes and a slowed repair rate in this DNA-dependent protein kinase catalytic subunit mutant suggest that the fast repair of double-strand breaks in telomeric DNA repeats during late prophase I is largely mediated by canonical nonhomologous end joining.