Department of Biochemistry & Structural Biology, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
Department of Biology, University of Iowa, Iowa City, IA 52242, USA.
DNA Repair (Amst). 2024 Oct;142:103759. doi: 10.1016/j.dnarep.2024.103759. Epub 2024 Aug 30.
Break-induced replication (BIR) is a homologous recombination (HR) pathway that repairs one-ended DNA double-strand breaks (DSBs), which can result from replication fork collapse, telomere erosion, and other events. Eukaryotic BIR has been mainly investigated in yeast, where it is initiated by invasion of the broken DNA end into a homologous sequence, followed by extensive replication synthesis proceeding to the chromosome end. Multiple recent studies have described BIR in mammalian cells, the properties of which show many similarities to yeast BIR. While HR is considered as "error-free" mechanism, BIR is highly mutagenic and frequently leads to chromosomal rearrangements-genetic instabilities known to promote human disease. In addition, it is now recognized that BIR is highly stimulated by replication stress (RS), including RS constantly present in cancer cells, implicating BIR as a contributor to cancer genesis and progression. Here, we discuss the past and current findings related to the mechanism of BIR, the association of BIR with replication stress, and the destabilizing effects of BIR on the eukaryotic genome. Finally, we consider the potential for exploiting the BIR machinery to develop anti-cancer therapeutics.
断裂诱导复制（BIR）是一种同源重组（HR）途径，可修复单链 DNA 双链断裂（DSBs），这些断裂可能是复制叉崩溃、端粒磨损和其他事件引起的。真核生物的 BIR 主要在酵母中进行研究，它是由断裂 DNA 末端侵入同源序列引发的，随后进行广泛的复制合成，直至染色体末端。最近的多项研究描述了哺乳动物细胞中的 BIR，其特性与酵母 BIR 有许多相似之处。虽然 HR 被认为是“无差错”的机制，但 BIR 具有高度的突变性，并且经常导致染色体重排——这些遗传不稳定性已知会促进人类疾病。此外，现在人们认识到，BIR 受到复制应激（RS）的强烈刺激，包括癌细胞中持续存在的 RS，这表明 BIR 是癌症发生和进展的一个因素。在这里，我们讨论了与 BIR 机制、BIR 与复制应激的关联以及 BIR 对真核基因组的不稳定性影响相关的过去和当前发现。最后，我们考虑利用 BIR 机制开发抗癌治疗方法的潜力。
