Inheritance of paternal DNA damage by histone-mediated repair restriction.
Siyao WangDavid H MeyerBjörn SchumacherPublished in: Nature (2022)
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 germline 1 , 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 F 1 generation from ionizing radiation-treated P 0 males, consequently improving the viability of the F 2 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.
Keyphrases
- dna repair
- dna damage
- high fat diet
- dna methylation
- healthcare
- circulating tumor
- endothelial cells
- genome wide
- single molecule
- public health
- oxidative stress
- mental health
- mitochondrial dna
- escherichia coli
- cell free
- adipose tissue
- working memory
- gene expression
- risk assessment
- weight loss
- radiation therapy
- papillary thyroid
- insulin resistance
- body mass index
- small molecule
- health promotion
- squamous cell
- lymph node metastasis
- birth weight
- radiation induced
- circulating tumor cells
- high frequency
- binding protein
- social media
- preterm birth