Targeting the Polycomb Machinery in BAP1-related Pathologies

BAP1-related mutations are common genetic lesions of several cancers and neurodevelopmental disorders (NDDs).

BAP1 is a deubiquitinase that removes the repressive mono-ubiquitination at histone H2AK119 (H2Aub1) deposited by the Polycomb Repressive Complex 1 (PRC1) by associating with several regulatory subunits to form the Polycomb Repressive Deubiquitinase (PR-DUB) complex.BAP1 inactivating mutations represent a hallmark in Malignant Mesothelioma (MM) for which genetic models proved its oncogenic role.

Mutations further extend to several other cancers, also involving other essential PR-DUB regulatory subunits.

This makes PR-DUB inactivation a major oncogenic event with ~40k new diagnosis each year between EU and US for which no precision therapeutic approaches exist.

The work of my Dissect-PcG ERC project found that the major role of BAP1 is to counteract H2Aub1 diffusion across the entire chromatin.

This preserves chromatin plasticity enhancing Polycomb-mediated control of transcriptional identity, which is decommissioned when BAP1 is inactivated and oncogenic H2Aub1 accumulates.

We also found that diffused H2Aub1 is controlled by a specific form of PRC1 - namely PRC1.3/5 - immediately suggesting a strategy to “correct” the effects of BAP1-related mutations.

Indeed, we found that specific PRC1.3/5 loss restored normal H2Aub1 levels while compromising MM cells viability, demonstrating the therapeutic potential of targeting this non-essential arm of PRC1 repressive machinery.By building a multidisciplinary team, the T-BAP project aims to develop compounds that can target PRC1.3/5 in living cells.

We propose to use PRC1.3/5 structural data to identify specific binders that can function as warheads for the development of PROTAC degraders.

This will generate a new class of molecules for the development of therapeutic strategies that can aid oncological patients with BAP1-related mutations, with a further potential application in specific NDD syndromes.