One of the most persistent issues in radiation biology relates to how paternal exposure to Ionising Radiation (IR) impacts genetic inheritance and disease risk in the progeny. The transgenerational consequences of Ionising Radiation (IR) exposure have been debated, and the processes remain elusive, despite the fact that 80% of transmitted mutations in humans originate in the paternal germline. Here, we demonstrate that paternal, but not maternal, IR radiation causes transgenerational embryonic mortality in sex-separated C. elegans strains. Several manifestations of genomic instability, such as DNA fragmentation, chromosomal rearrangement, and aneuploidy, were seen in the offspring of irradiated males. We found that maternally given errorprone polymerase-theta mediated end joining repairs paternal DNA Double Strand Breaks (DSBs) (TMEJ). We demonstrate the mechanism by which loss of a heterochromatin protein, HPL-1, or a human histone H1.0 ortholog, HIS-24, could significantly reverse the transgenerational embryonic lethality. By enabling the use of error-free Homologous Recombination Repair (HRR) in the germline of the F1 of IR-treated P0 males, removal of HIS-24 or HPL-1 decreased the heterochromatin marker histone 3 lysine 9 dimethylation (H3K9me2) and increased the viability of the F2 generationoverlap.
