The intrinsically disordered region of the E3 ubiquitin ligase TRIP12 induces the formation of chromatin condensates and interferes with DNA damage response.

Chromatin compaction is crucial for the expression and the integrity of the genome. We previously showed that the nuclear HECT-type E3 ubiquitin ligase TRIP12 (Thyroid hormone Receptor Interacting Protein 12) is tightly associated to chromatin. Overexpressed in several types of cancers, we explored herein the consequences of TRIP12 overexpression on chromatin homeostasis. First, we established the proxisome of TRIP12 by BioID and unveiled its pleiotropic role in chromatin regulation. Second, we demonstrated that an overexpression of TRIP12, via its intrinsically disordered region, leads to the formation of chromatin condensates enriched in heterochromatin epigenetic marks. We further discovered that the formation of TRIP12 mediated-chromatin condensates is highly dynamic and driven by a mechanism of polymer-polymer phase separation (PPPS). Chromatin condensates formation is dependent not only on the concentration, the length of TRIP12-IDR but also electrostatic interactions. Chromatin compaction is a determinant parameter in several biological processes. Indeed, we measured that the formation of TRIP12 mediated-chromatin condensates alters cell cycle progression, genome accessibility, transcription as well as DNA damage response (DDR) by inhibiting the accumulation of Mediator DNA Damage Checkpoint (MDC1). Altogether, this study reveals a novel dynamic role for TRIP12 in chromatin compaction independently of its ubiquitin ligase activity with important consequences on cellular processes.