Reference - Detail
| RRC ID | 76320 |
|---|---|
| Author | Wang S, Meyer DH, Schumacher B. |
| Title | Inheritance of paternal DNA damage by histone-mediated repair restriction. |
| Journal | Nature |
| Abstract |
How paternal exposure to ionizing radiation affects genetic inheritance and disease risk in the offspring has been a long-standing question in radiation biology. In humans, nearly 80% of transmitted mutations arise in the paternal germline1, but the transgenerational effects of ionizing radiation exposure has remained controversial and the mechanisms are unknown. Here we show that in sex-separated Caenorhabditis elegans 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. Paternal DNA 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 offspring, which may lead to congenital disorders and cancer in humans. |
| Volume | 613(7943) |
| Pages | 365-374 |
| Published | 2023-1-1 |
| DOI | 10.1038/s41586-022-05544-w |
| PII | 10.1038/s41586-022-05544-w |
| PMID | 36544019 |
| PMC | PMC9834056 |
| MeSH | Animals Caenorhabditis elegans* / embryology Caenorhabditis elegans* / genetics Caenorhabditis elegans* / radiation effects DNA Breaks, Double-Stranded / radiation effects DNA Damage* / radiation effects DNA End-Joining Repair DNA Polymerase theta DNA Repair* Embryo Loss / genetics Female Genomic Instability / radiation effects Histones* / metabolism Humans Male Mutation Radiation, Ionizing |
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 415 |
| Altmetric score changes over past 6months | 0.5 |
| Resource | |
| C.elegans | tm1145 tm1524 tm2026 |