Canitrot Y, Cazaux C, Fréchet M, Bouayadi K, Lesca C, Salles B, Hoffmann J S
Institut de Pharmacologie et Biologie Structurale, Unité Propre de Recherche Centre National de la Recherche Scientifique 9062, 31077 Toulouse cédex, France.
Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12586-90. doi: 10.1073/pnas.95.21.12586.
DNA polymerase beta (pol beta) is the most error prone of all known eukaryotic DNA polymerases tested in vitro. Here, we show that cells overexpressing pol beta cDNA have acquired a spontaneous mutator phenotype. By measuring the appearance of mutational events using three independent assays, we found that genetic instability increased in the cell lines that overexpressed pol beta. In addition, these cells displayed a decreased sensitivity to cancer chemotherapeutic, bifunctional, DNA-damaging agents such as cisplatin, melphalan, and mechlorethamine, resulting in enhanced mutagenesis compared with control cells. By using cell-free extracts and modified DNA substrates, we present data in support of error-prone translesion replication as one of the key determinants of tolerance phenotype. These results have implications for the potential role of pol beta overexpression in cancer predisposition and tumor progression during chemotherapy.
DNA聚合酶β（polβ）是在体外测试的所有已知真核DNA聚合酶中最易出错的。在此，我们表明过表达polβ cDNA的细胞获得了自发突变体表型。通过使用三种独立检测方法测量突变事件的出现情况，我们发现过表达polβ的细胞系中遗传不稳定性增加。此外，这些细胞对癌症化疗药物、双功能DNA损伤剂（如顺铂、美法仑和氮芥）的敏感性降低，与对照细胞相比导致诱变增强。通过使用无细胞提取物和修饰的DNA底物，我们提供的数据支持易错跨损伤复制作为耐受表型的关键决定因素之一。这些结果对polβ过表达在化疗期间癌症易感性和肿瘤进展中的潜在作用具有启示意义。
