Transgenerational Inheritance of Paternal DNA Damage by Linker Histone H1-mediated DNA Repair Restriction

Abstract How paternal exposure to ionizing radiation (IR) affects genetic inheritance and disease risk in the offspring has been one of the most long-standing questions in radiation biology. While in humans, 80% of transmitted mutations arise in the paternal germline, the transgenerational effects of ionizing radiation (IR)-exposure has remained controversial and the mechanisms elusive. Here, we show that in sex-separated C. elegans strains paternal, but not maternal, IR-exposure leads to a transgenerational embryonic lethality. Offspring of irradiated males displayed various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement, and aneuploidy. We determined that paternal DNA double strand breaks (DSBs) are repaired by maternally provided error-prone polymerase-theta mediated end joining (TMEJ). Mechanistically, we show that depletion of a human histone H1.0 ortholog, HIS-24, or the heterochromatin protein, HPL-1, could significantly reverse the transgenerational embryonic lethality. Removal of HIS-24 or HPL-1 reduced the heterochromatin marker histone 3 lysine 9 di-methylation (H3K9me2) and allowed the employment of the error-free Homologous Recombination Repair (HRR) in the germline of the F1 of IR-treated P0 males, consequently improving the viability of the F2 generation. Our work establishes the mechanistic underpinnings of transgenerational consequences of paternal radiation exposure on the health of offspring, which may lead to congenital disorders and cancer in humans.