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
Affiliations
Gabriel Fenteany
Institute of Genetics, Biological Research Centre, 6726 Szeged, Hungary; Corresponding author
Gaurav Sharma
HCEMM-BRC Mutagenesis and Carcinogenesis Research Group, Institute of Genetics, Biological Research Centre, 6726 Szeged, Hungary; Doctoral School of Biology, Faculty of Science and Informatics, University of Szeged, 6726 Szeged, Hungary
Paras Gaur
HCEMM-BRC Mutagenesis and Carcinogenesis Research Group, Institute of Genetics, Biological Research Centre, 6726 Szeged, Hungary
Attila Borics
Laboratory of Chemical Biology, Institute of Biochemistry, Biological Research Centre, 6726 Szeged, Hungary
Edit Wéber
Laboratory of Chemical Biology, Institute of Biochemistry, Biological Research Centre, 6726 Szeged, Hungary
Ernő Kiss
Institute of Genetics, Biological Research Centre, 6726 Szeged, Hungary
Lajos Haracska
HCEMM-BRC Mutagenesis and Carcinogenesis Research Group, Institute of Genetics, Biological Research Centre, 6726 Szeged, Hungary; Delta Bio 2000 Ltd., 6726 Szeged, Hungary; Corresponding author
Summary: 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.
