Repetitive DNA sequences are often associated with chromosomal rearrangements in cancers. Conventionally, single-strand annealing (SSA) is thought to mediate homology-directed repair of double-strand breaks (DSBs) between two repeats, causing repeat-mediated deletion (RMD). In this report, we demonstrate that break-induced replication (BIR) is used predominantly over SSA in mammalian cells for mediating RMD, especially when repeats are far apart. We show that SSA becomes inefficient in mammalian cells when the distance between the DSBs and the repeats is increased to the 1-2 kb range, while BIR-mediated RMD (BIR/RMD) can act over a long distance (e.g., ~ 100-200 kb) when the DSB is close to one repeat. Importantly, oncogene expression potentiates BIR/RMD but not SSA, and BIR/RMD is used more frequently at single-ended DSBs formed at collapsed replication forks than at double-ended DSBs. In contrast to short-range SSA, H2AX is required for long-range BIR/RMD, and sequence divergence strongly suppresses BIR/RMD in a manner partially dependent on MSH2. Our finding that BIR/RMD has a more important role than SSA in mammalian cells has a significant impact on the understanding of repeat-mediated rearrangements associated with oncogenesis.

中文翻译：

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断裂诱导的复制在远程重复介导的缺失中起重要作用。

重复的DNA序列通常与癌症中的染色体重排有关。常规上，单链退火（SSA）被认为可以介导两个重复序列之间由同源性指导的双链断裂（DSB）修复，从而导致重复介导的缺失（RMD）。在本报告中，我们证明了在哺乳动物细胞中，SSA主要用于破坏诱导复制（BIR）来介导RMD，尤其是当重复序列相距较远时。我们显示，当DSB与重复序列之间的距离增加到1-2 kb范围时，SSA在哺乳动物细胞中效率低下，而BIR介导的RMD（BIR / RMD）可以作用很长的距离（例如〜100- DSB接近一个重复时（200 kb）。重要的是，癌基因表达可增强BIR / RMD，但不能增强SSA，BIR / RMD在折叠复制叉形成的单端DSB上比在双端DSB上使用得更频繁。与短距离SSA相比，长距离BIR / RMD需要H2AX，并且序列发散会以部分依赖于MSH2的方式强烈抑制BIR / RMD。我们的发现BIR / RMD在哺乳动物细胞中比SSA具有更重要的作用，这对理解与肿瘤发生有关的重复介导的重排具有重要影响。