Selfish DNA modules like transposable elements (TEs) are particularly active in the germline, the lineage that passes genetic information across generations. New TE insertions can disrupt genes and impair the functionality and viability of germ cells. However, we found that in P–M hybrid dysgenesis in Drosophila, a sterility syndrome triggered by the P-element DNA transposon, germ cells harbor unexpectedly few new TE insertions despite accumulating DNA double-strand breaks (DSBs) and inducing cell cycle arrest. Using an engineered CRISPR–Cas9 system, we show that generating DSBs at silenced P-elements or other noncoding sequences is sufficient to induce germ cell loss independently of gene disruption. Indeed, we demonstrate that both developing and adult mitotic germ cells are sensitive to DSBs in a dosage-dependent manner. Following the mitotic-to-meiotic transition, however, germ cells become more tolerant to DSBs, completing oogenesis regardless of the accumulated genome damage. Our findings establish DNA damage tolerance thresholds as crucial safeguards of genome integrity during germline development.

中文翻译：

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耐受阈值是种系发育过程中对 DNA 损伤反应的基础


像转座元件 (TE) 这样的自私 DNA 模块在种系（将遗传信息代代相传的谱系）中特别活跃。新的 TE 插入会破坏基因并损害生殖细胞的功能和活力。然而，我们发现，在果蝇的P - M杂种发育不全（一种由P元件 DNA 转座子引发的不育综合征）中，尽管积累了 DNA 双链断裂（DSB）并诱导细胞周期停滞，生殖细胞却意外地很少有新的 TE 插入。使用工程改造的 CRISPR-Cas9 系统，我们证明在沉默的P元件或其他非编码序列处生成 DSB 足以诱导生殖细胞损失，而与基因破坏无关。事实上，我们证明发育中的和成体的有丝分裂生殖细胞都以剂量依赖性方式对 DSB 敏感。然而，在有丝分裂到减数分裂的转变之后，生殖细胞对 DSB 变得更加耐受，无论基因组损伤是否累积，都能完成卵子发生。我们的研究结果将 DNA 损伤耐受阈值确定为种系发育过程中基因组完整性的重要保障。