Top1-flox Mouse

Top1, short for Topoisomerase I, is a Type IB enzyme in eukaryotes. It is essential for managing the torsional stress associated with DNA strand separation during transcription and DNA replication. By resolving transcription-associated torsional stress, it reduces the accumulation of genome-destabilizing R-loops and non-B DNA structures. However, its DNA nicking activity can also initiate genome instability [2].

TOP1 inhibitors, like camptothecin derivatives (irinotecan, topotecan), are used in cancer treatment. Exatecan, a camptothecin derivative, shows stronger TOP1 trapping, higher DNA damage, and apoptotic cell death compared to classical TOP1 inhibitors. SLFN11 expression and homologous recombination (HR) deficiency can be predictive biomarkers for response to exatecan, and it synergistically kills cancer cells with ATR inhibitors [1].

In breast cancer, antibody-drug conjugate sacituzumab govitecan (SG), which contains a TOP1 inhibitor SN-38, enables a sequential TOP1/PARP inhibitor therapy strategy. Sequential dosing of SG followed by talazoparib (TZP) is a viable strategy while concurrent dosing has dose-limiting toxicities [4].

In triple-negative breast cancer (TNBC), dynamic temporal profiles of ATR/Chk1, JNK activation, and MYC expression may predict cancer cell response to TOP1 inhibitors. JNK-mediated MYC upregulation may govern cancer cell sensitivity to TOP1-targeting therapy [5].

In SARS-CoV-2 infection, TOP1 inhibition by topotecan suppresses lethal inflammation, suggesting its potential as a host-directed therapy [3].

In sleep-deprived mice, TOP1 in microglia mediates IL-6 release, leading to neuronal damage, and neopterin promotes TOP1 elevation by disrupting YY1 and HDAC1 binding [6].

In conclusion, Top1 plays a dual-edged role in maintaining genome stability. Its inhibitors have shown potential in treating various diseases, especially cancer. Studies using different models, though not specifically KO/CKO mouse models in these references, have provided insights into its functions in disease-related processes, such as inflammation, tumor growth, and neuronal damage. Understanding Top1 and its inhibitors may offer new therapeutic strategies for these diseases.