A recognized source of disease-causing genome alterations is erroneous repair of broken chromosomes, which can be executed by two distinct mechanisms: non-homologous end joining (NHEJ) and the recently discovered polymerase theta-mediated end joining (TMEJ) pathway. While TMEJ has previously been considered to act as an alternative mechanism backing up NHEJ, recent work points to a role for TMEJ in the repair of replication-associated DNA breaks that are excluded from repair through homologous recombination. Because of its mode of action, TMEJ is intrinsically mutagenic and sometimes leaves behind a recognizable genomic scar when joining chromosome break ends (i.e., ‘templated insertions’). This review article focuses on the intriguing observation that this polymerase theta signature is frequently observed in disease alleles, arguing for a prominent role of this double-strand break repair pathway in genome diversification and disease-causing spontaneous mutagenesis in humans.

导致疾病的基因组改变的一个公认来源是断裂染色体的错误修复，这可以通过两种不同的机制执行：非同源末端连接（NHEJ）和最近发现的聚合酶θ介导的末端连接（TMEJ）途径。虽然 TMEJ 之前被认为是支持 NHEJ 的替代机制，但最近的研究表明 TMEJ 在修复复制相关 DNA 断裂中发挥作用，这些断裂通过同源重组被排除在修复之外。由于其作用方式，TMEJ 本质上具有诱变性，有时在连接染色体断裂末端（即“模板插入”）时会留下可识别的基因组疤痕。这篇综述文章重点关注了一个有趣的观察结果，即这种聚合酶 theta 特征在疾病等位基因中经常观察到，认为这种双链断裂修复途径在人类基因组多样化和致病自发突变中发挥着重要作用。