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A shared ‘vulnerability code’ underpins varying sources of DNA damage throughout paternal germline transmission in mouse

Burden, Frances, Ellis, Peter J.I., Farré, Marta (2023) A shared ‘vulnerability code’ underpins varying sources of DNA damage throughout paternal germline transmission in mouse. Nucleic Acids Research, 51 (5). pp. 2319-2332. ISSN 0305-1048. E-ISSN 1362-4962. (doi:10.1093/nar/gkad089) (KAR id:100153)


During mammalian spermatogenesis, the paternal genome is extensively remodelled via replacement of histones with protamines forming the highly compact mature sperm nucleus. Compaction occurs in post-meiotic spermatids and is accompanied by extensive double strand break (DSB) formation. We investigate the epigenomic and genomic context of mouse spermatid DSBs, identifying primary sequence motifs, secondary DNA structures and chromatin contexts associated with this damage. Consistent with previously published results we find spermatid DSBs positively associated with short tandem repeats and LINE elements. We further show spermatid DSBs preferentially occur in association with (CA)n, (NA)n and (RY)n repeats, in predicted Z-DNA, are not associated with G-quadruplexes, are preferentially found in regions of low histone mark coverage and engage the remodelling/NHEJ factor BRD4. Locations incurring DSBs in spermatids also show distinct epigenetic profiles throughout later developmental stages: regions retaining histones in mature sperm, regions susceptible to oxidative damage in mature sperm, and fragile two-cell like embryonic stem cell regions bound by ZSCAN4 all co-localise with spermatid DSBs and with each other. Our results point to a common ‘vulnerability code’ unifying several types of DNA damage occurring on the paternal genome during reproduction, potentially underpinned by torsional changes during sperm chromatin remodelling.

Item Type: Article
DOI/Identification number: 10.1093/nar/gkad089
Additional information: For the purpose of open access, the author(s) has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising.
Uncontrolled keywords: Genetics
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
Funders: Leverhulme Trust (
Depositing User: Marta Farre Belmonte
Date Deposited: 20 Feb 2023 15:08 UTC
Last Modified: 12 Dec 2023 12:19 UTC
Resource URI: (The current URI for this page, for reference purposes)

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