PubReading [268] - Inheritance of paternal DNA damage by histone-mediated repair restriction - S. Wang, D. Meyer & B. Schumacher

<p>How paternal exposure to <strong>ionizing radiation</strong> affects genetic inheritance and disease risk in the offspring has been a long-standing question in radiation biology. In humans, nearly 80% of transmitted <strong>mutations</strong> arise in the paternal germline<a href="https://www.nature.com/articles/s41586-022-05544-w#ref-CR1">1</a>, but the transgenerational effects of ionizing radiation exposure has remained controversial and the mechanisms are unknown. Here we show that in sex-separated <em>Caenorhabditis elegans</em> strains, paternal, but not maternal, exposure to ionizing radiation leads to transgenerational embryonic lethality. The offspring of irradiated males displayed various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement and aneuploidy. <strong>Paternal DNA</strong> double strand breaks were repaired by maternally provided error-prone polymerase theta-mediated end joining. Mechanistically, we show that depletion of an orthologue of human histone H1.0, HIS-24, or the heterochromatin protein HPL-1, could significantly reverse the transgenerational embryonic lethality. Removal of HIS-24 or HPL-1 reduced histone 3 lysine 9 dimethylation and enabled error-free homologous recombination repair in the germline of the F1 generation from ionizing radiation-treated P0 males, consequently improving the viability of the F2 generation. This work establishes the mechanistic underpinnings of the heritable consequences of paternal radiation exposure on the health of <strong>offspring</strong>, which may lead to congenital disorders and cancer in humans.</p><p><a href="https://doi.org/10.1038/s41586-022-05544-w"><em>https://doi.org/10.1038/s41586-022-05544-w</em></a><em> - 2022</em></p>