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<p>DNA repair in human embryos is poorly understood, and double-strand breaks (DSBs) can cause chromosome loss. We show that chromosomal alterations relative to an induced DSB are asymmetric: acentric arms show complementary gains and losses, while centric arms are biased toward losses. Centromeric to the cut site secondary breakage and attrition is extensive. In contrast, break sites at acentric arms are conserved with no secondary breakage. These differences reflect differential forces at the mitotic spindle. Telomeric arms detach from the pro-metaphase spindle while centric truncated chromosomes lag during anaphase, suggesting that the DSB impedes sister chromatid separation. Secondary breakage near the centromere concordant with extensive attrition at the DSB site indicates a DSB can destabilize a chromosome without end-joining of sister chromatids. These results highlight the risks of chromosomal-scale changes in CRISPR-Cas9 genome editing and show that a single DSB can destabilize a human embryo chromosome independent of fusion-breakage cycles.</p>

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Asymmetric attrition and secondary chromosome destabilization after double-strand breaks in human embryonic development

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月3日

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  • Jenna Turocy,
  • Stepan Jerabek,
  • Woonyung Hur,
  • Jimin Kim,
  • Shuangyi Xu,
  • Qiaojin Zhao,
  • Jia Xu,
  • Alex Robles,
  • Xiangyi Liu,
  • Nathan Treff,
  • Diego Marin,
  • Anna-Katerina Hadjantonakis,
  • Dieter Egli

摘要

DNA repair in human embryos is poorly understood, and double-strand breaks (DSBs) can cause chromosome loss. We show that chromosomal alterations relative to an induced DSB are asymmetric: acentric arms show complementary gains and losses, while centric arms are biased toward losses. Centromeric to the cut site secondary breakage and attrition is extensive. In contrast, break sites at acentric arms are conserved with no secondary breakage. These differences reflect differential forces at the mitotic spindle. Telomeric arms detach from the pro-metaphase spindle while centric truncated chromosomes lag during anaphase, suggesting that the DSB impedes sister chromatid separation. Secondary breakage near the centromere concordant with extensive attrition at the DSB site indicates a DSB can destabilize a chromosome without end-joining of sister chromatids. These results highlight the risks of chromosomal-scale changes in CRISPR-Cas9 genome editing and show that a single DSB can destabilize a human embryo chromosome independent of fusion-breakage cycles.