Homologous recombination (HR), considered the highest fidelity DNA double-strand break (DSB) repair pathway that a cell possesses, is capable of repairing multiple DSBs without altering genetic information. However, in “last resort” scenarios, HR can be directed to low fidelity subpathways which often use non-allelic donor templates. Such repair mechanisms are often highly mutagenic and can also yield chromosomal rearrangements and/or deletions. While the choice between HR and its less precise counterpart, non-homologous end joining (NHEJ), has received much attention, less is known about how cells manage and prioritize HR subpathways. In this review, we describe work focused on how chromatin and nuclear architecture orchestrate subpathway choice and repair template usage to maintain genome integrity without sacrificing cell survival. Understanding the relationships between nuclear architecture and recombination mechanics will be critical to understand these cellular repair decisions.

同源重组 (HR) 被认为是细胞拥有的最高保真度 DNA 双链断裂 (DSB) 修复途径，能够在不改变遗传信息的情况下修复多个 DSB。然而，在“最后手段”的情况下，HR 可以被引导至通常使用非等位基因供体模板的低保真度子路径。这种修复机制通常具有高度诱变性，并且还可以产生染色体重排和/或缺失。虽然 HR 及其不太精确的对应物非同源末端连接 (NHEJ) 之间的选择受到了广泛关注，但人们对细胞如何管理和优先考虑 HR 子路径知之甚少。在这篇综述中，我们描述的工作重点是染色质和核结构如何协调子通路选择和修复模板的使用，以维持基因组完整性而不牺牲细胞存活。了解核结构和重组机制之间的关系对于理解这些细胞修复决策至关重要。