A series of xanthenes inhibiting Rad6 function and Rad6-Rad18 interaction in the PCNA ubiquitination cascade

Gabriel Fenteany; Gaurav Sharma; Paras Gaur; Attila Borics; Edit Wéber; Ernő Kiss; Lajos Haracska

doi:10.1016/j.isci.2022.104053

A series of xanthenes inhibiting Rad6 function and Rad6-Rad18 interaction in the PCNA ubiquitination cascade

iScience. 2022 Mar 10;25(4):104053. doi: 10.1016/j.isci.2022.104053. eCollection 2022 Apr 15.

Authors

Gabriel Fenteany¹, Gaurav Sharma^{2

3}, Paras Gaur², Attila Borics⁴, Edit Wéber⁴, Ernő Kiss¹, Lajos Haracska^{2

5}

Affiliations

¹ Institute of Genetics, Biological Research Centre, 6726 Szeged, Hungary.
² HCEMM-BRC Mutagenesis and Carcinogenesis Research Group, Institute of Genetics, Biological Research Centre, 6726 Szeged, Hungary.
³ Doctoral School of Biology, Faculty of Science and Informatics, University of Szeged, 6726 Szeged, Hungary.
⁴ Laboratory of Chemical Biology, Institute of Biochemistry, Biological Research Centre, 6726 Szeged, Hungary.
⁵ Delta Bio 2000 Ltd., 6726 Szeged, Hungary.

Abstract

Ubiquitination of proliferating cell nuclear antigen (PCNA) triggers pathways of DNA damage tolerance, including mutagenic translesion DNA synthesis, and comprises a cascade of reactions involving the E1 ubiquitin-activating enzyme Uba1, the E2 ubiquitin-conjugating enzyme Rad6, and the E3 ubiquitin ligase Rad18. We report here the discovery of a series of xanthenes that inhibit PCNA ubiquitination, Rad6∼ubiquitin thioester formation, and the Rad6-Rad18 interaction. Structure-activity relationship experiments across multiple assays reveal chemical and structural features important for different activities along the pathway to PCNA ubiquitination. The compounds that inhibit these processes are all a subset of the xanthen-3-ones we tested. These small molecules thus represent first-in-class probes of Rad6 function and the association of Rad6 and Rad18, the latter being a new inhibitory activity discovered for a small molecule, in the PCNA ubiquitination cascade and potential therapeutic agents to contain cancer progression.

Keywords: Cancer; Molecular biology.