Inheritance of paternal DNA damage by histone-mediated repair restriction

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.

Involvement of H2A variants in DNA damage response of zygotes

“…In recent years, there has been a growing interest in the alternative end joining (alt-EJ) repair pathway, which is implicated in mutagenesis during cancer development because it is less faithful than the two major DNA repair pathways in somatic cells: non-homologous end joining (NHEJ) and homologous recombination (HR) [ 42 ]. In nematode zygotes, irradiation-induced random DSBs in the paternal genome are predominantly repaired by the maternally provided error-prone alt-EJ and, notably, condensed chromatin prevents the use of the more faithful HR-dependent repair pathway, leading to high transgenerational lethality [ 43 ]. Zebrafish embryos show alt-EJ dominance in repairing DSBs induced by the CRISPR system [ 44 ].…”

HMGN1 loss sensitizes lung cancer cells to chemotherapy

“…HMGN1 supports repair of DNA lesions, it would be expected that histone H1 will have an opposite effect on DNA damage repair. Indeed, a number of studies suggest that histone H1 has an inhibitory effect on repair of DNA lesions 36 , 37 . Another investigation indicates that histone H1 suppresses repair of DSB in vitro when present in high concentrations 38 .…”

Increased male investment in sperm competition results in reduced maintenance of gametes

“…This in turn may steer female choice away from these males in order to enhance the genetic quality of offspring [ 84 ]. However, systematic differences in male and female expression of genes involved in germline maintenance, as indicated here, and the capacity of females to repair damaged male sperm [ 6 , 85 , 86 ] opens up for the possibility that females instead may devote large amounts of resources to maintenance of ejaculates and sperm deriving from males that are superior in sperm competition. Thus, male–female coevolution of germline maintenance may represent an important, yet understudied, aspect in the evolution of mate choice.…”