Homologous recombination (HR) is a universal DNA double-strand break (DSB) repair pathway that uses an intact DNA molecule as a template. Signature HR reactions are homology search and DNA strand invasion catalyzed by the prototypical RecA-ssDNA filament (Rad51 and Dmc1 in eukaryotes), which produces heteroduplex DNA-containing joint molecules (JMs). These reactions uniquely infringe on the DNA strands association established at replication, on the basis of substantial sequence similarity. For that reason, and despite the high fidelity of its templated nature, DSB repair by HR authorizes the alteration of genome structure, guided by repetitive DNA elements. The resulting structural variations (SVs) can involve vast genomic regions, potentially affecting multiple coding sequences and regulatory elements at once, with possible pathological consequences. Here, we discuss recent advances in our understanding of genetic and molecular vulnerabilities of HR leading to SVs, and of the various fidelity-enforcing factors acting across scales on the balancing act of this complex pathway. An emphasis is put on extra-chomosomal DNAs, both product of, and substrate for HR-mediated chromosomal rearrangements.

同源重组 (HR) 是一种通用的 DNA 双链断裂 (DSB) 修复途径，它使用完整的 DNA 分子作为模板。签名 HR 反应是由原型 RecA-ssDNA 丝（真核生物中的 Rad51 和 Dmc1）催化的同源性搜索和 DNA 链入侵，它产生含有异源双链 DNA 的关节分子 (JM)。基于大量序列相似性，这些反应独特地侵犯了在复制时建立的 DNA 链结合。出于这个原因，尽管其模板性质的高保真度，HR 的 DSB 修复授权在重复 DNA 元素的指导下改变基因组结构。由此产生的结构变异 (SV) 可能涉及巨大的基因组区域，可能同时影响多个编码序列和调控元件，具有可能的病理后果。在这里，我们讨论了我们对导致 SV 的 HR 的遗传和分子脆弱性的理解的最新进展，以及在这个复杂途径的平衡行为中跨尺度作用的各种保真执行因素。重点放在染色体外 DNA，既是 HR 介导的染色体重排的产物，也是底物。