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Small-molecules that bind to the ubiquitin-binding motif of REV1 inhibit REV1 interaction with K164-monoubiquitinated PCNA and suppress DNA damage tolerance
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2018-03-19 , DOI: 10.1016/j.bmc.2018.03.028
Murugendra Vanarotti , Benjamin J. Evison , Marcelo L. Actis , Akira Inoue , Ezelle T. McDonald , Youming Shao , Richard J. Heath , Naoaki Fujii

REV1 protein is a mutagenic DNA damage tolerance (DDT) mediator and encodes two ubiquitin-binding motifs (i.e., UBM1 and UBM2) that are essential for the DDT function. REV1 interacts with K164-monoubiquitinated PCNA (UbPCNA) in cells upon DNA-damaging stress. By using AlphaScreen assays to detect inhibition of REV1 and UbPCNA protein interactions along with an NMR-based strategy, we identified small-molecule compounds that inhibit the REV1/UbPCNA interaction and that directly bind to REV1 UBM2. In cells, one of the compound prevented recruitment of REV1 to PCNA foci on chromatin upon cisplatin treatment, delayed removal of UV-induced cyclopyrimidine dimers from nuclei, prevented UV-induced mutation of HPRT gene, and diminished clonogenic survival of cells that were challenged by cyclophosphamide or cisplatin. This study demonstrates the potential utility of a small-molecule REV1 UBM2 inhibitor for preventing DDT.



中文翻译:

结合REV1泛素结合基序的小分子抑制REV1与K164单泛素化PCNA的相互作用并抑制DNA损伤耐受性

REV1蛋白是一种诱变的DNA损伤耐受(DDT)介体,编码两个对于DDT功能必不可少的泛素结合基序(即UBM1和UBM2)。REV1在破坏DNA的压力下与细胞中的K164单泛素化PCNA(UbPCNA)相互作用。通过使用AlphaScreen分析检测对REV1和UbPCNA蛋白质相互作用的抑制以及基于NMR的策略,我们鉴定了抑制REV1 / UbPCNA相互作用并直接与REV1 UBM2结合的小分子化合物。在细胞中,该化合物之一阻止了顺铂处理后REV1募集到染色质上的PCNA病灶,延迟从细胞核中去除了UV诱导的环嘧啶二聚体,防止了UV诱导的HPRT基因突变,以及降低了受挑战的细胞的克隆形成存活率环磷酰胺或顺铂。

更新日期:2018-03-19
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