Universität zu Köln

Wang, Siyao, Meyer, David H. ORCID: 0000-0002-5667-4720 and Schumacher, Bjoern (2023). Inheritance of paternal DNA damage by histone-mediated repair restriction. Nature, 613 (7943). S. 365 - 393. BERLIN: NATURE PORTFOLIO. ISSN 1476-4687

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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 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wang, Siyao UNSPECIFIED UNSPECIFIED UNSPECIFIED Meyer, David H. UNSPECIFIED orcid.org/0000-0002-5667-4720 UNSPECIFIED Schumacher, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-660233
DOI:	10.1038/s41586-022-05544-w
Journal or Publication Title:	Nature
Volume:	613
Number:	7943
Page Range:	S. 365 - 393
Date:	2023
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	1476-4687
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DE-NOVO MUTATIONS; CHROMOSOMAL MOSAICISM; END; GERMLINE; HETEROCHROMATIN; MECHANISMS; INDUCTION; RADIATION; VARIANTS; LEUKEMIA Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66023