Black Samuel J, Kashkina Ekaterina, Kent Tatiana, Pomerantz Richard T
Fels Institute for Cancer Research, Department of Medical Genetics and Molecular Biochemistry, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
Genes (Basel). 2016 Sep 21;7(9):67. doi: 10.3390/genes7090067.
The gene encoding DNA polymerase θ (Polθ) was discovered over ten years ago as having a role in suppressing genome instability in mammalian cells. Studies have now clearly documented an essential function for this unique A-family polymerase in the double-strand break (DSB) repair pathway alternative end-joining (alt-EJ), also known as microhomology-mediated end-joining (MMEJ), in metazoans. Biochemical and cellular studies show that Polθ exhibits a unique ability to perform alt-EJ and during this process the polymerase generates insertion mutations due to its robust terminal transferase activity which involves template-dependent and independent modes of DNA synthesis. Intriguingly, the POLQ gene also encodes for a conserved superfamily 2 Hel308-type ATP-dependent helicase domain which likely assists in alt-EJ and was reported to suppress homologous recombination (HR) via its anti-recombinase activity. Here, we review our current knowledge of Polθ-mediated end-joining, the specific activities of the polymerase and helicase domains, and put into perspective how this multifunctional enzyme promotes alt-EJ repair of DSBs formed during S and G2 cell cycle phases.
十多年前发现了编码DNA聚合酶θ（Polθ）的基因，该基因在抑制哺乳动物细胞基因组不稳定性方面发挥作用。现在的研究已经清楚地证明，这种独特的A家族聚合酶在多细胞动物的双链断裂（DSB）修复途径——替代末端连接（alt-EJ，也称为微同源性介导的末端连接，MMEJ）中具有重要功能。生化和细胞研究表明，Polθ具有执行alt-EJ的独特能力，在此过程中，由于其强大的末端转移酶活性，聚合酶会产生插入突变，该活性涉及DNA合成的模板依赖性和非依赖性模式。有趣的是，POLQ基因还编码一个保守的超家族2 Hel308型ATP依赖性解旋酶结构域，该结构域可能有助于alt-EJ，并且据报道通过其抗重组酶活性抑制同源重组（HR）。在这里，我们回顾了我们目前对Polθ介导的末端连接、聚合酶和解旋酶结构域的特定活性的了解，并探讨了这种多功能酶如何促进在S期和G2期细胞周期阶段形成的DSB的alt-EJ修复。
