Mammalian cells have evolved multiple pathways to repair DNA double strand breaks (DSBs) and ensure genome stability. In addition to non-homologous end-joining (NHEJ) and homologous recombination (HR), cells evolved an error-prone repair pathway termed microhomology-mediated end joining (MMEJ). The mutagenic outcome of MMEJ derives from the activity of DNA polymerase theta (Polθ) - a multidomain enzyme that is minimally expressed in normal tissue but overexpressed in tumors. Polθ expression is particularly crucial for the proliferation of HR deficient cancer cells. As a result, this mutagenic repair emerged as an attractive target for cancer therapy, and inhibitors are currently in pre-clinical development. Here, we review the multifunctionality of this enigmatic polymerase, focusing on its role during DSB repair in mammalian cells and its impact on cancer genomes.

中文翻译：

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DNA 聚合酶 theta (Polθ) - 一种容易出错的聚合酶，对于基因组稳定性至关重要。


哺乳动物细胞已经进化出多种途径来修复 DNA 双链断裂 (DSB) 并确保基因组稳定性。除了非同源末端连接（NHEJ）和同源重组（HR）之外，细胞还进化出一种容易出错的修复途径，称为微同源介导的末端连接（MMEJ）。 MMEJ 的诱变结果源自 DNA 聚合酶 theta (Polθ) 的活性，这是一种多域酶，在正常组织中表达最低，但在肿瘤中过度表达。 Polθ 表达对于 HR 缺陷癌细胞的增殖尤其重要。因此，这种诱变修复成为癌症治疗的一个有吸引力的靶点，抑制剂目前正处于临床前开发阶段。在此，我们回顾了这种神秘聚合酶的多功能性，重点关注其在哺乳动物细胞 DSB 修复过程中的作用及其对癌症基因组的影响。