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by claude@2026-07, 2026-07-06
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The paper investigated how unrepaired nucleotide lesions at stalled replication forks lead to clastogenesis, using wild-type, nucleotide excision repair (NER)-deficient, and translesion synthesis (TLS)-deficient cells together with advanced cytogenetic analyses. The authors found that ssDNA tracts containing unrepaired lesions can persist through mitosis without being converted into DSBs, and only in the following S phase are they transformed into a new class of highly clastogenic DSBs, rather than DSBs at collapsed forks directly driving rearrangements. A caveat is that the mechanism was largely established in cell systems, with implications for how genome rearrangements arise in tumors rather than direct in vivo verification. The study links to disease biology by noting that prostate cancers with extensive genomic rearrangements frequently show somatic defects in NER or error-free homologous recombination-mediated DSB repair. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Damaged DNA nucleotides can trigger genome rearrangements through clastogenesis, a process driven by erroneous repair of double-strand breaks (DSBs) and associated with cancer development. While DSBs are known to arise from endonuclease activity at stalled replication forks, the clastogenic potential of such DSBs has remained uncertain. Here, we identify a previously unrecognized mechanism of clastogenesis using wild-type, nucleotide excision repair (NER)-deficient and translesion synthesis (TLS)-deficient cells, combined with advanced cytogenetic analyses. We demonstrate that, single-stranded DNA (ssDNA) tracts harboring unrepaired lesions rather than DSBs at collapsed replication forks can persist through mitosis. Only during the subsequent S phase, these tracts are converted into a new class of, highly clastogenic, DSBs. Consistent with a role of this mechanism in carcinogenesis, prostate cancers exhibiting extensive genomic rearrangements frequently harbor somatic defects in NER or in error-free homologous recombination-mediated DSB repair. These findings provide critical mechanistic insight and highlight potential implications for routine clastogenicity testing. Graphical abstract Nucleotide lesions (light blue triangle) can trigger double-strand breaks (DSBs) through endonucleolytic cleavage at stalled or reversed replication forks. Traditionally, these DSBs were assumed to drive genome rearrangements, a process termed clastogenesis. Here we describe a distinct, delayed, mechanism of clastogenesis. Thus, unreplicated nucleotide lesions within single-stranded (ss) DNA regions persist through mitosis into the next cell cycle. During the subsequent S phase, these ssDNA tracts collapse into DSBs, presumably via replication runoff. These delayed DSBs then promote extensive genomic reshuffling. Supporting this model, prostate cancers with high levels of genomic rearrangements are frequently associated with somatic defects in nucleotide excision repair (NER)—a pathway that normally prevents lesion-induced clastogenesis.
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Abstract
Damaged DNA nucleotides can trigger genome rearrangements through clastogenesis, a process driven by erroneous repair of double-strand breaks (DSBs) and associated with cancer development. While DSBs are known to arise from endonuclease activity at stalled replication forks, the clastogenic potential of such DSBs has remained uncertain. Here, we identify a previously unrecognized mechanism of clastogenesis using wild-type, nucleotide excision repair (NER)-deficient and translesion synthesis (TLS)-deficient cells, combined with advanced cytogenetic analyses. We demonstrate that, single-stranded DNA (ssDNA) tracts harboring unrepaired lesions rather than DSBs at collapsed replication forks can persist through mitosis. Only during the subsequent S phase, these tracts are converted into a new class of, highly clastogenic, DSBs. Consistent with a role of this mechanism in carcinogenesis, prostate cancers exhibiting extensive genomic rearrangements frequently harbor somatic defects in NER or in error-free homologous recombination-mediated DSB repair. These findings provide critical mechanistic insight and highlight potential implications for routine clastogenicity testing.
Graphical abstract Nucleotide lesions (light blue triangle) can trigger double-strand breaks (DSBs) through endonucleolytic cleavage at stalled or reversed replication forks. Traditionally, these DSBs were assumed to drive genome rearrangements, a process termed clastogenesis. Here we describe a distinct, delayed, mechanism of clastogenesis. Thus, unreplicated nucleotide lesions within single-stranded (ss) DNA regions persist through mitosis into the next cell cycle. During the subsequent S phase, these ssDNA tracts collapse into DSBs, presumably via replication runoff. These delayed DSBs then promote extensive genomic reshuffling. Supporting this model, prostate cancers with high levels of genomic rearrangements are frequently associated with somatic defects in nucleotide excision repair (NER)—a pathway that normally prevents lesion-induced clastogenesis.
Competing Interest Statement
The authors have declared no competing interest.
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