Four repair pathways process DNA double-strand breaks (DSBs). Among these pathways the homologous recombination repair (HRR) subpathway of gene conversion (GC) affords error-free processing, but functions only in S- and G2-phases of the cell cycle. Classical non-homologous end-joining (c-NHEJ) operates throughout the cell cycle, but causes small deletions and translocations. Similar deficiencies in exaggerated form, combined with reduced efficiency, are associated with alternative end-joining (alt-EJ). Finally, single-strand annealing (SSA) causes large deletions and possibly translocations. Thus, processing of a DSB by any pathway, except GC, poses significant risks to the genome, making the mechanisms navigating pathway-engagement critical to genome stability. Logically, the cell ought to attempt engagement of the pathway ensuring preservation of the genome, while accommodating necessities generated by the types of DSBs induced. Thereby, inception of DNA end-resection will be key determinant for GC, SSA and alt-EJ engagement. We reported that during G2-phase, where all pathways are active, GC engages in the processing of almost 50 % of DSBs, at low DSB-loads in the genome, and that this contribution rapidly drops to nearly zero with increasing DSB-loads. At the transition between these two extremes, SSA and alt-EJ compensate, but at extremely high DSB-loads resection-dependent pathways are suppressed and c-NHEJ remains mainly active. We inquired whether in this processing framework all DSBs have similar fates. Here, we analyze in G2-phase the processing of a subset of DSBs defined by their ability to break chromosomes. Our results reveal an absolute requirement for GC in the processing of chromatid breaks at doses in the range of 1 Gy. Defects in c-NHEJ delay significantly the inception of processing by GC, but leave processing kinetics unchanged. These results delineate the essential role of GC in chromatid break repair before mitosis and classify DSBs that underpin this breakage as the exclusive substrate of GC.

中文翻译：

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由低剂量的G2相电离辐射产生的染色体断裂仅通过基因转换来处理。

四个修复途径处理DNA双链断裂（DSB）。在这些途径中，基因转化（GC）的同源重组修复（HRR）子途径可提供无错误的处理，但仅在细胞周期的S期和G2期起作用。经典的非同源末端连接（c-NHEJ）在整个细胞周期中均起作用，但会引起小的缺失和易位。夸张形式的类似缺陷以及降低的效率与替代的端接（alt-EJ）相关。最后，单链退火（SSA）导致大的缺失和可能的易位。因此，通过除GC以外的任何途径处理DSB会对基因组造成重大风险，从而使通过途径参与的机制对于基因组稳定性至关重要。从逻辑上讲 细胞应尝试参与确保基因组保存的途径，同时适应由诱导的DSB类型产生的必需品。因此，DNA末端切除的开始将是GC，SSA和alt-EJ参与的关键决定因素。我们报告说，在G2阶段，所有途径均处于激活状态，在基因组中低DSB负载下，GC参与了将近50％的DSB的加工，并且随着DSB负载的增加，这一贡献迅速降至几乎为零。在这两个极端之间的过渡时，SSA和alt-EJ会补偿，但是在极高的DSB负载下，切除依赖的途径会受到抑制，而c-NHEJ仍主要活跃。我们询问在此处理框架中是否所有DSB都有相似的命运。这里，我们在G2阶段分析DSB子集的处理过程，这些子集由其破坏染色体的能力定义。我们的结果表明，在处理1 Gy范围内的染色单体断裂时，GC绝对必要。c-NHEJ的缺陷显着延迟了GC处理的开始，但处理动力学保持不变。这些结果描述了GC在有丝分裂之前染色单体断裂修复中的重要作用，并将支撑该断裂的DSBs分类为GC的唯一底物。