TOP1 诱导的 DNA 损伤的过程和修复中 TDP1 非依赖性途径。

TDP1-independent pathways in the process and repair of TOP1-induced DNA damage.

机构信息

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

出版信息

Nat Commun. 2022 Jul 22;13(1):4240. doi: 10.1038/s41467-022-31801-7.

Anticancer drugs, such as camptothecin (CPT), trap topoisomerase I (TOP1) on DNA and form TOP1 cleavage complexes (TOP1cc). Alternative repair pathways have been suggested in the repair of TOP1cc. However, how these pathways work with TDP1, a key repair enzyme that specifically hydrolyze the covalent bond between TOP1 catalytic tyrosine and the 3'-end of DNA and contribute to the repair of TOP1cc is poorly understood. Here, using unbiased whole-genome CRISPR screens and generation of co-deficient cells with TDP1 and other genes, we demonstrate that MUS81 is an important factor that mediates the generation of excess double-strand breaks (DSBs) in TDP1 KO cells. APEX1/2 are synthetic lethal with TDP1. However, deficiency of APEX1/2 does not reduce DSB formation in TDP1 KO cells. Together, our data suggest that TOP1cc can be either resolved directly by TDP1 or be converted into DSBs and repaired further by the Homologous Recombination (HR) pathway.

抗癌药物，如喜树碱（CPT），将拓扑异构酶 I（TOP1）捕获在 DNA 上并形成 TOP1 切割复合物（TOP1cc）。已提出替代修复途径来修复 TOP1cc。然而，对于 TDP1 这种关键的修复酶，它特异性地水解 TOP1 催化酪氨酸与 DNA 3'-末端之间的共价键，并有助于修复 TOP1cc 的途径，我们知之甚少。在这里，我们使用无偏的全基因组 CRISPR 筛选和 TDP1 与其他基因的共缺陷细胞的生成，证明 MUS81 是介导 TDP1 KO 细胞中过多双链断裂（DSB）产生的重要因素。APEX1/2 与 TDP1 合成致死。然而，APEX1/2 的缺陷并不能减少 TDP1 KO 细胞中的 DSB 形成。总之，我们的数据表明 TOP1cc 可以直接被 TDP1 解决，也可以转化为 DSBs 并进一步通过同源重组（HR）途径修复。