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by claude@2026-07, 2026-07-04
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The paper develops a canavanine-based counter-selection reporter assay in fission yeast to detect gross chromosomal rearrangements (GCRs) in a chromosomal context and uses it to map genome instability hotspots. Using this assay, the authors find natural GCR hotspots including inverted long terminal repeats (IR-LTRs); they report that IR-LTR–induced events mainly yield terminal deletions with adjacent inverted duplications or occur via long-range break-induced replication (BIR), with BIR reaching up to 600 kb, and that deleting IR-LTRs uncovers an additional BIR-driven hotspot between homeologous aldo/keto reductase genes. They also test modulators of genome instability, reporting that loss of the nuclear pore component Nup132 increases IR-LTR–induced GCRs while disrupting djc9 decreases overall GCR rates. The paper’s primary limitation is that its findings are generated in a fission yeast system using an assay that targets specific sequence motifs and reporter contexts. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Abstract/Summary Gross chromosomal rearrangements are a hallmark of many diseases and cancers. The study of their biogenesis and the mechanisms underlying their formation is greatly facilitated by the availability of genetic reporter assays in model organisms. We present here a novel GCR assay developed in fission yeast, a highly relevant model for understanding genome instability related to human biology. The reporter employs canavanine counter-selection to detect GCRs within a chromosomal context. Using this assay, we identified natural hotspots for GCRs, including inverted long terminal repeats (IR-LTRs). Structural analysis of GCR events showed that IR-LTR–induced GCRs mainly result in either terminal deletions with adjacent inverted duplications or repair via long-range break-induced replication (BIR). Deleting IR-LTRs reduces the GCR rate and reveals another hotspot driven by BIR between homeologous aldo/keto reductase genes on opposite arms of chromosome I. This is the first evidence that BIR can occur in S. pombe on long tracks reaching up to 600 kb. Besides highlighting genome rearrangement hotspots, the assay also identifies regulators of genome instability in fission yeast. Loss of Nup132, a component of the nuclear pore complex, increases IR-LTRs-induced GCRs, while the budding yeast homolog Nup133 has no effect on the stability of a structurally similar IR. In contrast, disrupting djc9 , which encodes a conserved histone H3–H4 binding protein, decreases GCR rates. Overall, this sensitive GCR assay enables the identification of factors that control spontaneous and fragile motif–induced chromosomal instability, including those conserved in humans but lost through evolution in other organisms.
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Abstract/Summary
Gross chromosomal rearrangements are a hallmark of many diseases and cancers. The study of their biogenesis and the mechanisms underlying their formation is greatly facilitated by the availability of genetic reporter assays in model organisms. We present here a novel GCR assay developed in fission yeast, a highly relevant model for understanding genome instability related to human biology. The reporter employs canavanine counter-selection to detect GCRs within a chromosomal context. Using this assay, we identified natural hotspots for GCRs, including inverted long terminal repeats (IR-LTRs). Structural analysis of GCR events showed that IR-LTR–induced GCRs mainly result in either terminal deletions with adjacent inverted duplications or repair via long-range break-induced replication (BIR). Deleting IR-LTRs reduces the GCR rate and reveals another hotspot driven by BIR between homeologous aldo/keto reductase genes on opposite arms of chromosome I. This is the first evidence that BIR can occur in S. pombe on long tracks reaching up to 600 kb. Besides highlighting genome rearrangement hotspots, the assay also identifies regulators of genome instability in fission yeast. Loss of Nup132, a component of the nuclear pore complex, increases IR-LTRs-induced GCRs, while the budding yeast homolog Nup133 has no effect on the stability of a structurally similar IR. In contrast, disrupting djc9, which encodes a conserved histone H3–H4 binding protein, decreases GCR rates. Overall, this sensitive GCR assay enables the identification of factors that control spontaneous and fragile motif–induced chromosomal instability, including those conserved in humans but lost through evolution in other organisms.
Competing Interest Statement
The authors have declared no competing interest.
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