Department of Molecular Biology, Ariel University, Ariel 40700, Israel.
Azrieli Faculty of Medicine, Bar Ilan University, Safed 52900, Israel.
Molecules. 2022 Jan 19;27(3):636. doi: 10.3390/molecules27030636.
DNA-damaging chemotherapy agents such as cisplatin have been the first line of treatment for cancer for decades. While chemotherapy can be very effective, its long-term success is often reduced by intrinsic and acquired drug resistance, accompanied by chemotherapy-resistant secondary malignancies. Although the mechanisms causing drug resistance are quite distinct, they are directly connected to mutagenic translesion synthesis (TLS). The TLS pathway promotes DNA damage tolerance by supporting both replication opposite to a lesion and inaccurate single-strand gap filling. Interestingly, inhibiting TLS reduces both cisplatin resistance and secondary tumor formation. Therefore, TLS targeting is a promising strategy for improving chemotherapy. MAD2L2 (i.e., Rev7) is a central protein in TLS. It is an essential component of the TLS polymerase zeta (ζ), and it forms a regulatory complex with Rev1 polymerase. Here we present the discovery of two small molecules, c#2 and c#3, that directly bind both in vitro and in vivo to MAD2L2 and influence its activity. Both molecules sensitize lung cancer cell lines to cisplatin, disrupt the formation of the MAD2L2-Rev1 complex and increase DNA damage, hence underlining their potential as lead compounds for developing novel TLS inhibitors for improving chemotherapy treatments.
数十年来，DNA 损伤化疗药物（如顺铂）一直是癌症的一线治疗药物。虽然化疗可能非常有效，但由于内在和获得性耐药性，其长期疗效往往会降低，同时还伴有化疗耐药性的继发性恶性肿瘤。尽管导致耐药性的机制截然不同，但它们与诱变跨损伤合成（TLS）直接相关。TLS 途径通过支持与损伤相对的复制和不准确的单链间隙填充来促进 DNA 损伤容忍。有趣的是，抑制 TLS 可降低顺铂耐药性和继发性肿瘤形成。因此，TLS 靶向是提高化疗效果的有前途的策略。MAD2L2（即 Rev7）是 TLS 中的核心蛋白。它是 TLS 聚合酶 ζ 的必需组成部分，并与 Rev1 聚合酶形成调节复合物。在这里，我们发现了两种小分子 c#2 和 c#3，它们可直接在体外和体内与 MAD2L2 结合并影响其活性。这两种分子均能使肺癌细胞系对顺铂敏感，破坏 MAD2L2-Rev1 复合物的形成并增加 DNA 损伤，因此它们具有作为开发新型 TLS 抑制剂以改善化疗治疗的潜在先导化合物的潜力。
