A Series of Xanthenes Inhibiting Rad6 Function and Rad6-Rad18 Interaction in the PCNA Ubiquitination Cascade

Overview

Journal iScience

Publisher Cell Press

Date 2022 Mar 31

PMID 35355521

Authors

Gabriel Fenteany

Gaurav Sharma

Paras Gaur

Attila Borics

Edit Weber

Erno Kiss

Lajos Haracska

Affiliations

Soon will be listed here.

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.

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