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Cited by 68DNA Repair MechanismsEffects of Radiation ExposureEpigenetics and DNA Methylation

Inheritance of paternal DNA damage by histone-mediated repair restriction

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Wang, Siyao, Meyer, David H., Schumacher, Björn·2023·Nature
DOI 10.1038/s41586-022-05544-wPMC PMC9834056

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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.

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  • In cancer genomes, single nucleotide variants are preferentially accumulated in heterochromatin because condensed structure presents a barrier to efficient DNA repair.

    “in cancer genome single nucleotide variants are preferentially accumulated in heterochromatin, due to the condensed structure presents as a barrier for efficient DNA repair10,47”

    From Single-cell parallel analysis of DNA damage and transcriptome reveals selective genome vulnerability (2025) · cites this paper as [10]

    The ‘HRR prevents transgenerational lethality’ section says heterochromatization could impede faithful double-strand-break repair, supporting the proposed repair barrier. But the paper’s evidence concerns paternal DNA damage and structural variants, not preferential accumulation of single-nucleotide variants in heterochromatin in cancer genomes. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Reduced H3K9me2 levels facilitate homologous recombination repair.

    “reduced H3K9me2 levels facilitates homologous recombination repair10”

    From Single-cell parallel analysis of DNA damage and transcriptome reveals selective genome vulnerability (2025) · cites this paper as [10]

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Research works printed but not linked: 57

  1. [1]Kong A Rate of de novo mutations and the importance of father’s age to disease risk Nature 2012 488 471 475 10.1038/nature11396 22914163 PMC3548427 · DOI · Paper page
  2. [4]Vijg J Dong X Pathogenic mechanisms of somatic mutation and genome mosaicism in aging Cell 2020 182 12 23 10.1016/j.cell.2020.06.024 32649873 PMC7354350 · DOI
  3. [5]Wright, S. The Roles of Mutation, Inbreeding, Crossbreeding, and Selection in Evolution. In: Proc. of the XI International Congress of Genetics8, 209–222 (1932).
  4. [6]Hu C Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer JAMA 2018 319 2401 10.1001/jama.2018.6228 29922827 PMC6092184 · DOI · Paper page
  5. [7]Kloosterman WP Characteristics of de novo structural changes in the human genome Genome Res. 2015 25 792 801 10.1101/gr.185041.114 25883321 PMC4448676 · DOI
  6. [8]Belyeu JR De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families Am. J. Hum. Genet. 2021 108 597 607 10.1016/j.ajhg.2021.02.012 33675682 PMC8059337 · DOI
  7. [9]Malaspina D Paternal factors and schizophrenia risk: de novo mutations and imprinting Schizophr. Bull. 2001 27 379 393 10.1093/oxfordjournals.schbul.a006882 11596842 PMC2993009 · DOI
  8. [10]Cawthon RM Germline mutation rates in young adults predict longevity and reproductive lifespan Sci. Rep. 2020 10 10001 10.1038/s41598-020-66867-0 32561805 PMC7305191 · DOI
  9. [11]Holtgrewe M Multisite de novo mutations in human offspring after paternal exposure to ionizing radiation Sci. Rep. 2018 8 14611 10.1038/s41598-018-33066-x 30279461 PMC6168503 · DOI
  10. [12]Dubrova YuE Mutation induction in the mouse and human germline Russ. J. Genet. 2016 52 17 28 10.1134/S1022795416010038 27183790 · DOI
  11. [13]Little MP Goodhead DT Bridges BA Bouffler SD Evidence relevant to untargeted and transgenerational effects in the offspring of irradiated parents Mutat. Res. 2013 753 50 67 10.1016/j.mrrev.2013.04.001 23648355 PMC3737396 · DOI
  12. [14]Gardner MJ Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria Brit. Med. J. 1990 300 423 429 10.1136/bmj.300.6722.423 2107892 PMC1662259 · DOI
  13. [15]Wakeford R Childhood leukaemia and radiation exposure of fathers-the end of the road, perhaps? J. Radiol. Prot. 2003 23 359 362 10.1088/0952-4746/23/4/E02 14750684 · DOI
  14. [16]Gardner MJ Hall AJ Downes S Terrell JD Follow up study of children born elsewhere but attending schools in Seascale, West Cumbria (schools cohort) Brit. Med. J. 1987 295 819 822 10.1136/bmj.295.6602.819 3119057 PMC1247862 · DOI
  15. [17]Yeager M Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident Science 2021 372 725 729 10.1126/science.abg2365 33888597 PMC9398532 · DOI
  16. [18]Morton LM Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident Science 2021 372 eabg2538 10.1126/science.abg2538 33888599 PMC9022889 · DOI
  17. [19]Kodaira M Satoh C Hiyama K Toyama K Lack of effects of atomic bomb radiation on genetic instability of tandem-repetitive elements in human germ cells Am. J. Hum. Genet. 1995 57 1275 8533756 PMC1801425
  18. [20]Kodaira M No evidence of increased mutation rates at microsatellite loci in offspring of A-bomb survivors Radiat. Res. 2010 173 205 213 10.1667/RR1991.1 20095853 · DOI
  19. [21]Kaplanis J Genetic and chemotherapeutic influences on germline hypermutation Nature 2022 605 503 508 10.1038/s41586-022-04712-2 35545669 PMC9117138 · DOI
  20. [22]Kaplanis J Evidence for 28 genetic disorders discovered by combining healthcare and research data Nature 2020 586 757 762 10.1038/s41586-020-2832-5 33057194 PMC7116826 · DOI · Paper page
  21. [23]Marchetti F Essers J Kanaar R Wyrobek AJ Disruption of maternal DNA repair increases sperm-derived chromosomal aberrations Proc. Natl Acad. Sci. USA 2007 104 17725 17729 10.1073/pnas.0705257104 17978187 PMC2077046 · DOI
  22. [24]McClintock B The stability of broken ends of chromosomes in Zea mays Genetics 1941 26 234 282 10.1093/genetics/26.2.234 17247004 PMC1209127 · DOI
  23. [25]Gartner A Milstein S Ahmed S Hodgkin J Hengartner MO A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans Mol. Cell 2000 5 435 443 10.1016/S1097-2765(00)80438-4 10882129 · DOI
  24. [26]Rappaport Y Bisection of the X chromosome disrupts the initiation of chromosome silencing during meiosis in Caenorhabditis elegans Nat. Commun. 2021 12 4802 10.1038/s41467-021-24815-0 34376665 PMC8355143 · DOI
  25. [27]Wyatt DW Essential roles for polymerase θ-mediated end joining in the repair of chromosome breaks Mol. Cell 2016 63 662 673 10.1016/j.molcel.2016.06.020 27453047 PMC4992412 · DOI
  26. [28]Roerink SF van Schendel R Tijsterman M Polymerase theta-mediated end joining of replication-associated DNA breaks in C. elegans Genome Res. 2014 24 954 962 10.1101/gr.170431.113 24614976 PMC4032859 · DOI
  27. [29]Burma S Chen BPC Chen DJ Role of non-homologous end joining (NHEJ) in maintaining genomic integrity DNA Repair 2006 5 1042 1048 10.1016/j.dnarep.2006.05.026 16822724 · DOI
  28. [30]Cook DE Zdraljevic S Roberts JP Andersen EC CeNDR, the Caenorhabditis elegans natural diversity resource Nucleic Acids Res. 2017 45 D650 D657 10.1093/nar/gkw893 27701074 PMC5210618 · DOI
  29. [31]Volkova NV Mutational signatures are jointly shaped by DNA damage and repair Nat. Commun. 2020 11 2169 10.1038/s41467-020-15912-7 32358516 PMC7195458 · DOI
  30. [32]Van Schendel R Roerink SF Portegijs V Van Den Heuvel S Tijsterman M Polymerase Θ is a key driver of genome evolution and of CRISPR/Cas9-mediated mutagenesis Nat. Commun. 2015 6 7394 10.1038/ncomms8394 26077599 PMC4490562 · DOI
  31. [33]Carvajal-Garcia J Mechanistic basis for microhomology identification and genome scarring by polymerase theta Proc. Natl Acad. Sci. USA 2020 117 8476 8485 10.1073/pnas.1921791117 32234782 PMC7165422 · DOI
  32. [34]Byrska-Bishop M High coverage whole genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios SSRN Electron. J. 2021 185 3426 3440.e19 PMC9439720 36055201
  33. [35]Jónsson H Parental influence on human germline de novo mutations in 1,548 trios from Iceland Nature 2017 549 519 522 10.1038/nature24018 28959963 · DOI · Paper page
  34. [36]Jedrusik-Bode M Histone H1 and heterochromatin protein 1 (HP1) regulate specific gene expression and not global transcription Worm 2013 2 e1002940 10.4161/worm.23703 PMC3704446 24058872 · DOI
  35. [37]Studencka M Transcriptional repression of Hox genes by C. elegans HP1/HPL and H1/HIS-24 PLoS Genet. 2012 8 e1002940 10.1371/journal.pgen.1002940 23028351 PMC3441639 · DOI
  36. [38]Lorković ZJ Berger F Heterochromatin and DNA damage repair: use different histone variants and relax Nucleus 2017 8 583 588 10.1080/19491034.2017.1384893 29077523 PMC5788557 · DOI
  37. [39]Cann KL Dellaire G Heterochromatin and the DNA damage response: the need to relax Biochem. Cell Biol. 2011 89 45 60 10.1139/O10-113 21326362 · DOI
  38. [40]Alpi A Pasierbek P Gartner A Loidl J Genetic and cytological characterization of the recombination protein RAD-51 in Caenorhabditis elegans Chromosoma 2003 112 6 16 10.1007/s00412-003-0237-5 12684824 · DOI
  39. [41]Dubrova YE Sarapultseva EI Radiation-induced transgenerational effects in animals Int. J. Radiat. Biol. 2020 98 1047 1053 10.1080/09553002.2020.1793027 32658553 · DOI
  40. [42]Middelkamp S Sperm DNA damage causes genomic instability in early embryonic development Sci. Adv. 2020 6 eaaz7602 10.1126/sciadv.aaz7602 32494621 PMC7159919 · DOI
  41. [43]Taylor TH The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans Hum. Reprod. Update 2014 20 571 581 10.1093/humupd/dmu016 24667481 · DOI
  42. [44]Spinella F Extent of chromosomal mosaicism influences the clinical outcome of in vitro fertilization treatments Fertil. Steril. 2018 109 77 83 10.1016/j.fertnstert.2017.09.025 29191449 · DOI
  43. [45]Lord B Tumour induction by methyl-nitroso-urea following preconceptional paternal contamination with plutonium-239 Br. J. Cancer 1998 78 301 311 10.1038/bjc.1998.491 9703275 PMC2063036 · DOI
  44. [46]Vorobtsova IE Aliyakparova LM Anisimov VN Promotion of skin tumors by 12-O-tetradecanoylphorbol-13-acetate in two generations of descendants of male mice exposed to X-ray irradiation Mutat. Res. Mol. Mech. Mutagen. 1993 287 207 216 10.1016/0027-5107(93)90013-6 7685480 · DOI
  45. [47]Makova KD Li W-H Strong male-driven evolution of DNA sequences in humans and apes Nature 2002 416 624 626 10.1038/416624a 11948348 · DOI
  46. [48]Goldmann JM Parent-of-origin-specific signatures of de novo mutations Nat. Genet. 2016 48 935 939 10.1038/ng.3597 27322544 · DOI
  47. [49]Roberti A Valdes AF Torrecillas R Fraga MF Fernandez AF Epigenetics in cancer therapy and nanomedicine Clin. Epigenetics 2019 11 81 10.1186/s13148-019-0675-4 31097014 PMC6524244 · DOI
  48. [50]Gartner, A., MacQueen, A. J. & Villeneuve, A. M. in Checkpoint Controls and Cancer vol. 280 (ed. Schönthal, A. H.) 257–274 (Humana, 2004).
  49. [51]Larance M Stable-isotope labeling with amino acids in nematodes Nat. Methods 2011 8 849 851 10.1038/nmeth.1679 21874007 PMC3184259 · DOI · Paper page
  50. [52]Seo B Lee J Observation and quantification of telomere and repetitive sequences using fluorescence in situ hybridization (FISH) with PNA probes in Caenorhabditis elegans J. Vis. Exp. 2016 114 e54224 PMC5091719 27583462
  51. [53]Yu G Wang L-G Han Y He Q-Y clusterProfiler: an R package for comparing biological themes among gene clusters OMICS 2012 16 284 287 10.1089/omi.2011.0118 22455463 PMC3339379 · DOI · Paper page
  52. [54]Chen S Zhou Y Chen Y Gu J fastp: an ultra-fast all-in-one FASTQ preprocessor Bioinformatics 2018 34 i884 i890 10.1093/bioinformatics/bty560 30423086 PMC6129281 · DOI
  53. [55]Li, H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. Preprint at 10.48550/arXiv.1303.3997 (2013). · DOI
  54. [56]Li H The Sequence Alignment/Map format and SAMtools Bioinformatics 2009 25 2078 2079 10.1093/bioinformatics/btp352 19505943 PMC2723002 · DOI · Paper page
  55. [58]Chen X Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications Bioinformatics 2016 32 1220 1222 10.1093/bioinformatics/btv710 26647377 · DOI
  56. [59]Gu Z Gu L Eils R Schlesner M Brors B circlize implements and enhances circular visualization in R Bioinformatics 2014 30 2811 2812 10.1093/bioinformatics/btu393 24930139 · DOI
  57. [60]Seabold, S. & Perktold, J. Statsmodels: Econometric and statistical modeling with Python. in Proc. of the 9th Python in Science Conference vol. 57 (SciPy, 2010).

Cited by

Sorted by citations

Authors
Wang, S., Meyer, D. H., & Schumacher, B.
Affiliations
University of Cologne (DE)
Corresponding author
  • Wang, Siyao
  • Schumacher, Björn
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2022-12-21
Volume
613
Issue
7943
Pages
365-374
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-022-05544-w
PMC
PMC9834056
OpenAlex
W4312095729
Cited by
68
References
2
Citations by year
2026: 12 · 2025: 18 · 2024: 16 · 2023: 21 · 2022: 1
FWCI
4.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • John Templeton Foundation (61734)
  • Oklahoma Medical Research Foundation
  • Deutsche Forschungsgemeinschaft (GRK-2407, SFB829, 390661388, SCHU 2494/11-1, 407493903, KFO286, SCHU 2494 15-1, EXC2030, SCHU 2494/7-1, KFO-329, SCHU 2494/3‐1, 423957469, SCHU 2494/10‐1)
  • Ministry of Education, Culture, Sports, Science and Technology
  • Deutsche Krebshilfe (70112899)
  • Universität zu Köln (EXC 2030 -390661388)
  • National Institutes of Health (H2020)
  • Horizon 2020 Framework Programme (MSCA‐ITN‐2018, H2020-MSCA, 390661388, H2020-MSCA-ITN-2018, H2020-MSCA-ITN)
  • National Center for Research Resources
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
transgenerational effects, DNA double-strand breaks, DNA repair, histone H1.0, H3K9me2, homologous recombination repair, polymerase theta, genomic instability, aneuploidy, chromosomal rearrangements, embryonic lethality, germline, Caenorhabditis elegans
MeSH terms
DNA Polymerase theta, Animals, Chromosomal Proteins, Non-Histone, DNA Damage, DNA Repair, Female, Histones, Humans, Male, Mutation, Radiation, Ionizing, Caenorhabditis elegans, Embryo Loss, Caenorhabditis elegans Proteins, Genomic Instability, DNA Breaks, Double-Stranded, DNA End-Joining Repair

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