Meiotic interstrand DNA damage escapes paternal repair and causes chromosomal aberrations in the zygote by maternal misrepair

Marchetti, Francesco; Bishop, Jack; Gingerich, John; Wyrobek, Andrew J.

doi:10.1038/srep07689

Title: Meiotic interstrand DNA damage escapes paternal repair and causes chromosomal aberrations in the zygote by maternal misrepair

Journal Article · Thu Jan 08 00:00:00 EST 2015 · Scientific Reports

DOI:https://doi.org/10.1038/srep07689· OSTI ID:1257269

Marchetti, Francesco ^[1]; Bishop, Jack ^[2]; Gingerich, John ^[3]; Wyrobek, Andrew J. ^[4]

Environmental Health Science Research Bureau, Health Canada, Ottawa, ON (Canada); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
National Institute of Environmental Health Sciences, Research Triangle Park, NC (United States). National Toxicology Program
Environmental Health Science Research Bureau, Health Canada, Ottawa, ON (Canada)
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

De novo point mutations and chromosomal structural aberrations (CSA) detected in offspring of unaffected parents show a preferential paternal origin with higher risk for older fathers. Studies in rodents suggest that heritable mutations transmitted from the father can arise from either paternal or maternal misrepair of damaged paternal DNA, and that the entire spermatogenic cycle can be at risk after mutagenic exposure. Understanding the susceptibility and mechanisms of transmission of paternal mutations is important in family planning after chemotherapy and donor selection for assisted reproduction. We report that treatment of male mice with melphalan (MLP), a bifunctional alkylating agent widely used in chemotherapy, induces DNA lesions during male mouse meiosis that persist unrepaired as germ cells progress through DNA repair-competent phases of spermatogenic development. After fertilization, unrepaired sperm DNA lesions are mis-repaired into CSA by the egg's DNA repair machinery producing chromosomally abnormal offspring. In conclusion, these findings highlight the importance of both pre- and post-fertilization DNA repair in assuring the genomic integrity of the conceptus.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-05CH11231; W-7405-END-48; Y01-ES-102-00

OSTI ID:: 1257269

Journal Information:: Scientific Reports, Vol. 5; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 42 works

Citation information provided by
Web of Science

References (47)

DNA damage and mutagenesis induced by nitrogen mustards Povirk, Lawrence F.; Shuker, David E. Mutation Research/Reviews in Genetic Toxicology, Vol. 318, Issue 3 https://doi.org/10.1016/0165-1110(94)90015-9	journal	December 1994
Chromosome abnormalities in human beings McFadden, Deborah E.; Friedman, J. M. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 396, Issue 1-2 https://doi.org/10.1016/s0027-5107(97)00179-6	journal	December 1997
Mechanism of Replication-Coupled DNA Interstrand Crosslink Repair Räschle, Markus; Knipscheer, Puck; Enoiu, Milica Cell, Vol. 134, Issue 6 https://doi.org/10.1016/j.cell.2008.08.030	journal	September 2008
Disruption of maternal DNA repair increases sperm-derived chromosomal aberrations Marchetti, F.; Essers, J.; Kanaar, R. Proceedings of the National Academy of Sciences, Vol. 104, Issue 45 https://doi.org/10.1073/pnas.0705257104	journal	October 2007
Repair of DNA interstrand cross-links Dronkert, Mies L. G.; Kanaar, Roland Mutation Research/DNA Repair, Vol. 486, Issue 4 https://doi.org/10.1016/S0921-8777(01)00092-1	journal	September 2001
γH2AX signalling during sperm chromatin remodelling in the mouse zygote Derijck, Alwin A. H. A.; van der Heijden, Godfried W.; Giele, Maud DNA Repair, Vol. 5, Issue 8 https://doi.org/10.1016/j.dnarep.2006.05.043	journal	August 2006
Repair of DNA interstrand cross-links during S phase of the mammalian cell cycle Legerski, Randy J. Environmental and Molecular Mutagenesis https://doi.org/10.1002/em.20566	journal	January 2010
DNA double-strand break repair in parental chromatin of mouse zygotes, the first cell cycle as an origin of de novo mutation Derijck, Alwin; van der Heijden, Godfried; Giele, Maud Human Molecular Genetics, Vol. 17, Issue 13 https://doi.org/10.1093/hmg/ddn090	journal	March 2008
A direct characterization of human mutation based on microsatellites Sun, James X.; Helgason, Agnar; Masson, Gisli Nature Genetics, Vol. 44, Issue 10 https://doi.org/10.1038/ng.2398	journal	August 2012
REV1 and DNA polymerase zeta in DNA interstrand crosslink repair Sharma, Shilpy; Canman, Christine E. Environmental and Molecular Mutagenesis, Vol. 53, Issue 9 https://doi.org/10.1002/em.21736	journal	October 2012
Effects of Male Germ-Cell Stage on the Frequency, Nature, and Spectrum of Induced Specific-Locus Mutations in the Mouse Russell, Liane B. Genetica, Vol. 122, Issue 1 https://doi.org/10.1007/s10709-004-1443-7	journal	September 2004
Unravelling meiotic chromosomes: topoisomerase II and other proteins Moens, Peter B. Journal of Cell Science, Vol. 97, Issue 1 https://doi.org/10.1242/jcs.97.1.1	journal	September 1990
Spermatogonial stem cell regulation and spermatogenesis Phillips, Bart T.; Gassei, Kathrin; Orwig, Kyle E. Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 365, Issue 1546 https://doi.org/10.1098/rstb.2010.0026	journal	May 2010
The origins, patterns and implications of human spontaneous mutation Crow, James F. Nature Reviews Genetics, Vol. 1, Issue 1 https://doi.org/10.1038/35049558	journal	October 2000
Expanded roles of the Fanconi anemia pathway in preserving genomic stability Kee, Y.; D'Andrea, A. D. Genes & Development, Vol. 24, Issue 16 https://doi.org/10.1101/gad.1955310	journal	August 2010
Specificity and kinetics of interstrand and intrastrand bifunctional alkylation by nitrogen mustards at a G-G-C sequence Bauer, G. Nucleic Acids Research, Vol. 25, Issue 6 https://doi.org/10.1093/nar/25.6.1211	journal	March 1997
DNA Double Strand Breaks but Not Interstrand Crosslinks Prevent Progress through Meiosis in Fully Grown Mouse Oocytes Yuen, Wai Shan; Merriman, Julie A.; O'Bryan, Moira K. PLoS ONE, Vol. 7, Issue 8 https://doi.org/10.1371/journal.pone.0043875	journal	August 2012
Melphalan, a second chemical for which specific-locus mutation induction in the mouse is maximum in early spermatids Russell, L. B.; Hunsicker, P. R.; Shelby, M. D. Mutation Research Letters, Vol. 282, Issue 3 https://doi.org/10.1016/0165-7992(92)90089-z	journal	July 1992
A new FISH assay to simultaneously detect structural and numerical chromosomal abnormalities in mouse sperm Hill, Francesca S.; Marchetti, Francesco; Liechty, Melissa Molecular Reproduction and Development, Vol. 66, Issue 2 https://doi.org/10.1002/mrd.10299	journal	August 2003
Etoposide induces chromosomal abnormalities in mouse spermatocytes and stem cell spermatogonia Marchetti, Francesco; Pearson, Francesca S.; Bishop, Jack B. Human Reproduction, Vol. 21, Issue 4 https://doi.org/10.1093/humrep/dei416	journal	November 2005
Cytogenetic technique for mouse metaphase II oocytes Mailhes, John B.; Yuan, Zhi Ping Gamete Research, Vol. 18, Issue 1 https://doi.org/10.1002/mrd.1120180109	journal	September 1987
How do male germ cells handle DNA damage? Olsen, A.; Lindeman, B.; Wiger, R. Toxicology and Applied Pharmacology, Vol. 207, Issue 2 https://doi.org/10.1016/j.taap.2005.01.060	journal	September 2005
Mammalian BTBD12 (SLX4) Protects against Genomic Instability during Mammalian Spermatogenesis Holloway, J. Kim; Mohan, Swapna; Balmus, Gabriel PLoS Genetics, Vol. 7, Issue 6 https://doi.org/10.1371/journal.pgen.1002094	journal	June 2011
DNA repair mechanisms and gametogenesis Baarends, Wm; van der Laan, R.; Grootegoed, Ja Reproduction https://doi.org/10.1530/rep.0.1210031	journal	January 2001
DNA interstrand crosslink repair and cancer Deans, Andrew J.; West, Stephen C. Nature Reviews Cancer, Vol. 11, Issue 7 https://doi.org/10.1038/nrc3088	journal	June 2011
Dominant lethal and heritable translocation tests with chlorambucil and melphalan in male mice Generoso, W. M.; Witt, Kristine L.; Cain, K. T. Mutation Research/Genetic Toxicology, Vol. 345, Issue 3-4 https://doi.org/10.1016/0165-1218(95)90052-7	journal	December 1995
DNA Damage Recognition in the Rat Zygote Following Chronic Paternal Cyclophosphamide Exposure Barton, Tara S.; Robaire, Bernard; Hales, Barbara F. Toxicological Sciences, Vol. 100, Issue 2 https://doi.org/10.1093/toxsci/kfm242	journal	September 2007
Genetics and human conception: DNA repair by oocytes Ashwood-Smith, M. J.; Edwards, R. G. Molecular Human Reproduction, Vol. 2, Issue 1 https://doi.org/10.1093/molehr/2.1.46	journal	January 1996
DNA adducts from chemotherapeutic agents Lawley, P. D.; Phillips, D. H. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 355, Issue 1-2 https://doi.org/10.1016/0027-5107(96)00020-6	journal	August 1996
Flow sorting of the mouse Cattanach X chromosome, T (X; 7) 1 Ct, in an active or inactive state Disteche, C. M.; Carrano, A. V.; Ashworth, L. K. Cytogenetic and Genome Research, Vol. 29, Issue 4 https://doi.org/10.1159/000131569	journal	January 1981
Rate of de novo mutations and the importance of father’s age to disease risk Kong, Augustine; Frigge, Michael L.; Masson, Gisli Nature, Vol. 488, Issue 7412 https://doi.org/10.1038/nature11396	journal	August 2012
Mechanisms and consequences of paternally-transmitted chromosomal abnormalities Marchetti, Francesco; Wyrobek, Andrew J. Birth Defects Research Part C: Embryo Today: Reviews, Vol. 75, Issue 2 https://doi.org/10.1002/bdrc.20040	journal	January 2005
Annual Report to the Nation on the Status of Cancer, 1975–2009, Featuring the Burden and Trends in Human Papillomavirus (HPV)–Associated Cancers and HPV Vaccination Coverage Levels Jemal, Ahmedin; Simard, Edgar P.; Dorell, Christina JNCI: Journal of the National Cancer Institute, Vol. 105, Issue 3 https://doi.org/10.1093/jnci/djs491	journal	January 2013
Mechanism of Replication-Coupled DNA Interstrand Crosslink Repair Markus, Räschle,; D., Griffith, Jack; Todor, Angelov, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/6751-sp75	text	January 2008
Genetic lesions induced by chemicals in spermatozoa and spermatids of mice are repaired in the egg. Generoso, W. M.; Cain, K. T.; Krishna, M. Proceedings of the National Academy of Sciences, Vol. 76, Issue 1 https://doi.org/10.1073/pnas.76.1.435	journal	January 1979
An Air-Drying Method for Meiotic Preparations from Mammalian Testes Evans, E. P.; Breckon, G.; Ford, C. E. Cytogenetic and Genome Research, Vol. 3, Issue 5 https://doi.org/10.1159/000129818	journal	January 1964
DNA repair decline during mouse spermiogenesis results in the accumulation of heritable DNA damage Marchetti, Francesco; Wyrobek, Andrew J. DNA Repair, Vol. 7, Issue 4 https://doi.org/10.1016/j.dnarep.2007.12.011	journal	April 2008
To err (meiotically) is human: the genesis of human aneuploidy Hassold, Terry; Hunt, Patricia Nature Reviews Genetics, Vol. 2, Issue 4 https://doi.org/10.1038/35066065	journal	April 2001
The role of DNA topoisomerases in recombination and genome stability: A double-edged sword? Wang, James C.; Caron, Paul R.; Kim, Raymond A. Cell, Vol. 62, Issue 3 https://doi.org/10.1016/0092-8674(90)90002-V	journal	August 1990
Nuclear basic proteins in spermiogenesis Wouters-Tyrou, D.; Martinage, A.; Chevaillier, P. Biochimie, Vol. 80, Issue 2 https://doi.org/10.1016/s0300-9084(98)80018-7	journal	February 1998
Etoposide induces heritable chromosomal aberrations and aneuploidy during male meiosis in the mouse Marchetti, F.; Bishop, J. B.; Lowe, X. Proceedings of the National Academy of Sciences, Vol. 98, Issue 7 https://doi.org/10.1073/pnas.061404598	journal	March 2001
Genetic, cytogenetic, and molecular analyses of mutations induced by melphalan demonstrate high frequencies of heritable deletions and other rearrangements from exposure of postspermatogonial stages of the mouse. Russell, L. B.; Hunsicker, P. R.; Cacheiro, N. L. Proceedings of the National Academy of Sciences, Vol. 89, Issue 13 https://doi.org/10.1073/pnas.89.13.6182	journal	July 1992
Significance of the perigametic interval as a major source of spontaneous mutations that result in mosaics Russell, Liane B. Environmental and Molecular Mutagenesis, Vol. 34, Issue 1 https://doi.org/10.1002/(SICI)1098-2280(1999)34:1<16::AID-EM3>3.0.CO;2-X	journal	January 1999
Semen quality and spermatozoal DNA integrity in survivors of childhood cancer: a case-control study Thomson, Angela B.; Campbell, Alastair J.; Irvine, D. Stewart The Lancet, Vol. 360, Issue 9330 https://doi.org/10.1016/S0140-6736(02)09606-X	journal	August 2002
Paternally Transmitted Chromosomal Aberrations in Mouse Zygotes Determine Their Embryonic Fate1 Marchetti, Francesco; Bishop, Jack B.; Cosentino, Lidia Biology of Reproduction, Vol. 70, Issue 3 https://doi.org/10.1095/biolreprod.103.023044	journal	March 2004
Resolving the role of topoisomerase II in chromatin structure and function Poljak, L. Trends in Cell Biology, Vol. 5, Issue 9 https://doi.org/10.1016/s0962-8924(00)89068-6	journal	September 1995
Unscheduled DNA synthesis assay in mammalian spermatogenic cells: An update Sotomayor, Rene E.; Sega, Gary A. Environmental and Molecular Mutagenesis, Vol. 36, Issue 4 https://doi.org/10.1002/1098-2280(2000)36:4<255::AID-EM1>3.0.CO;2-O	journal	January 2000

Cited By (13)

Aneuploidy: a common and early evidence-based biomarker for carcinogens and reproductive toxicants Mandrioli, Daniele; Belpoggi, Fiorella; Silbergeld, Ellen K. Environmental Health, Vol. 15, Issue 1 https://doi.org/10.1186/s12940-016-0180-6	journal	October 2016
DNA damage and repair in the female germline: contributions to ART Martin, Jacinta H.; Aitken, R. John; Bromfield, Elizabeth G. Human Reproduction Update, Vol. 25, Issue 2 https://doi.org/10.1093/humupd/dmy040	journal	December 2018
TUNEL assay: Establishing a sperm DNA fragmentation cut‐off value for Egyptian infertile men Hassanen, Eman; Elqusi, Khaled; Zaki, Hosam Andrologia, Vol. 51, Issue 10 https://doi.org/10.1111/and.13375	journal	July 2019
Mammalian sperm nuclear organization: resiliencies and vulnerabilities Champroux, A.; Torres-Carreira, J.; Gharagozloo, P. Basic and Clinical Andrology, Vol. 26, Issue 1 https://doi.org/10.1186/s12610-016-0044-5	journal	December 2016
Zygotic chromosomal structural aberrations after paternal drug treatment Robaire, Bernard; Downey, AnneMarie Asian Journal of Andrology, Vol. 17, Issue 6 https://doi.org/10.4103/1008-682x.154307	journal	January 2015
Tolerance to paternal genotoxic damage promotes survival during embryo development in zebrafish ( Danio rerio ) Fernández-Díez, Cristina; González-Rojo, Silvia; Lombó, Marta Biology Open, Vol. 7, Issue 5 https://doi.org/10.1242/bio.030130	journal	April 2018
Single and Double Strand Sperm DNA Damage: Different Reproductive Effects on Male Fertility Ribas-Maynou, Jordi; Benet, Jordi Genes, Vol. 10, Issue 2 https://doi.org/10.3390/genes10020105	journal	January 2019
Risk of Congenital Malformations in Children Born Before Paternal Cancer Al-Jebari, Yahia; Rylander, Lars; Ståhl, Olof JNCI Cancer Spectrum, Vol. 2, Issue 2 https://doi.org/10.1093/jncics/pky027	journal	April 2018
A Return to the Origin of the EMGS: Rejuvenating the Quest for Human Germ Cell Mutagens and Determining the Risk to Future Generations Marchetti, Francesco; Douglas, George R.; Yauk, Carole L. Environmental and Molecular Mutagenesis, Vol. 61, Issue 1 https://doi.org/10.1002/em.22327	journal	October 2019
Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study Al-Jebari, Yahia; Glimelius, Ingrid; Berglund Nord, Carina PLOS Medicine, Vol. 16, Issue 6 https://doi.org/10.1371/journal.pmed.1002816	journal	June 2019
Reduced sperm DNA longevity is associated with an increased incidence of still born; evidence from a multi-ovulating sequential artificial insemination animal model Johnston, Stephen D.; López-Fernández, Carmen; Arroyo, Francisca Journal of Assisted Reproduction and Genetics, Vol. 33, Issue 9 https://doi.org/10.1007/s10815-016-0754-9	journal	June 2016
Fatherhood and Sperm DNA Damage in Testicular Cancer Patients Paoli, Donatella; Pallotti, Francesco; Lenzi, Andrea Frontiers in Endocrinology, Vol. 9 https://doi.org/10.3389/fendo.2018.00506	journal	September 2018
Heat exposure induces oxidative stress and DNA damage in the male germ line† Houston, Brendan J.; Nixon, Brett; Martin, Jacinta H. Biology of Reproduction, Vol. 98, Issue 4 https://doi.org/10.1093/biolre/ioy009	journal	January 2018

Similar Records

How do male germ cells handle DNA damage?

Journal Article · Thu Sep 01 00:00:00 EDT 2005 · Toxicology and Applied Pharmacology · OSTI ID:1257269

Olsen, Ann-Karin; Lindeman, Birgitte; Wiger, Richard; +2 more

The stress response in gametes and embryos after paternal chemical exposures

Journal Article · Thu Sep 01 00:00:00 EDT 2005 · Toxicology and Applied Pharmacology · OSTI ID:1257269

Hales, Barbara F; Aguilar-Mahecha, Adriana; Robaire, Bernard

Genetics of x-ray induced double strand break repair in saccharomyces cerevisiae

Technical Report · Thu Jul 01 00:00:00 EDT 1982 · OSTI ID:1257269

Budd, M E

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
cytogenetics
development

Title: Meiotic interstrand DNA damage escapes paternal repair and causes chromosomal aberrations in the zygote by maternal misrepair

Citation Formats

References (47)

Cited By (13)

Similar Records

Related Subjects