PDF(Pubmed)
Abstract：
The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in creating single-stranded DNA gaps and inducing sensitivity requires the FANCJ DNA helicase. Yet, how FANCJ relates to PARP1 inhibition or trapping, which contribute to PARPi toxicity, remains unclear. Here, we find PARPi effectiveness hinges on S-phase PARP1 activity, which is reduced in FANCJ deficient cells as G-quadruplexes sequester PARP1 and MSH2. Additionally, loss of the FANCJ-MLH1 interaction diminishes PARP1 activity; however, depleting MSH2 reinstates PARPi sensitivity and gaps. Indicating sequestered and trapped PARP1 are distinct, FANCJ loss increases PARPi resistance in cells susceptible to PARP1 trapping. However, with BRCA1 deficiency, the loss of FANCJ mirrors PARP1 loss or inhibition, with the detrimental commonality being loss of S-phase PARP1 activity. These insights underline the crucial role of PARP1 activity during DNA replication in BRCA1 deficient cells and emphasize the importance of understanding drug mechanisms for enhancing therapeutic response.
摘要：
聚（ADP-核糖）聚合酶抑制剂（PARPi）在创建单链DNA缺口和诱导敏感性方面的有效性需要FANCJDNA解旋酶。然而，FANCJ如何与PARP1抑制或捕获相关，导致PARPi毒性，尚不清楚。这里,我们发现PARPi的有效性取决于PARP1的S期活性，其在FANCJ缺陷细胞中作为G-四链体螯合PARP1和MSH2而减少。此外,FANCJ-MLH1相互作用的丧失会降低PARP1活性；然而，耗尽MSH2可恢复PARPi灵敏度和间隙。表明隔离和捕获的PARP1是不同的，FANCJ损失增加对PARP1捕获敏感的细胞中的PARPi抗性。然而,BRCA1缺乏症，FANCJ的丢失反映了PARP1的丢失或抑制，不利的共性是失去S期PARP1活性。这些见解强调了PARP1活性在BRCA1缺陷细胞中DNA复制过程中的关键作用，并强调了理解药物机制对增强治疗反应的重要性。
