1. Nature. 2023 Jan;613(7943):365-374. doi: 10.1038/s41586-022-05544-w. Epub 2022 
Dec 21.

Inheritance of paternal DNA damage by histone-mediated repair restriction.

Wang S(1)(2), Meyer DH(3)(4), Schumacher B(5)(6).

Author information:
(1)Institute for Genome Stability in Aging and Disease, Medical Faculty, 
University Hospital and University of Cologne, Cologne, Germany. 
siyao.wang@uk-koeln.de.
(2)Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of 
Cologne, Cologne, Germany. siyao.wang@uk-koeln.de.
(3)Institute for Genome Stability in Aging and Disease, Medical Faculty, 
University Hospital and University of Cologne, Cologne, Germany.
(4)Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of 
Cologne, Cologne, Germany.
(5)Institute for Genome Stability in Aging and Disease, Medical Faculty, 
University Hospital and University of Cologne, Cologne, Germany. 
bjoern.schumacher@uni-koeln.de.
(6)Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated 
Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of 
Cologne, Cologne, Germany. bjoern.schumacher@uni-koeln.de.

Comment in
    Nature. 2023 Jan;613(7943):249-250.

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.

© 2022. The Author(s).

DOI: 10.1038/s41586-022-05544-w
PMCID: PMC9834056
PMID: 36544019 [Indexed for MEDLINE]

Conflict of interest statement: B.S. is a co-founder of Agevio Therapeutics.