The E3 ubiquitin ligase TRIP12 participates in cell cycle progression and chromosome stability

D Larrieu,J Torrisani,L Dagnon,N Hanoun,L Ligat,M Brunet,R M Pommier,H Lulka,J Selves,C Vargas,B E Jády,M Dufresne,L Bartholin,P Cordelier

doi:10.1038/s41598-020-57762-9

Abstract

Several studies have linked the E3 ubiquitin ligase TRIP12 (Thyroid hormone Receptor Interacting Protein 12) to the cell cycle. However, the regulation and the implication of this protein during the cell cycle are largely unknown. In this study, we show that TRIP12 expression is regulated during the cell cycle, which correlates with its nuclear localization. We identify an euchromatin-binding function of TRIP12 mediated by a N-terminal intrinsically disordered region. We demonstrate the functional implication of TRIP12 in the mitotic entry by controlling the duration of DNA replication that is independent from its catalytic activity. We also show the requirement of TRIP12 in the mitotic progression and chromosome stability. Altogether, our findings show that TRIP12 is as a new chromatin-associated protein with several implications in the cell cycle progression and in the maintenance of genome integrity.

Highlights

Several studies have linked the E3 ubiquitin ligase TRIP12 (Thyroid hormone Receptor Interacting Protein 12) to the cell cycle
We identified several intrinsically disordered regions (IDR) in the TRIP12 sequence that could potentially act as chromatin interacting-domains, notably one in the N-terminus located between the amino-acids 1 and 440 (Fig. 3A)
The E3 ubiquitin ligase TRIP12 was linked to the control of cell cycle regulators (i.e.: p14/ARF, p16/CDKN2A)[10]

Summary

Introduction

Several studies have linked the E3 ubiquitin ligase TRIP12 (Thyroid hormone Receptor Interacting Protein 12) to the cell cycle. Among the proteins that participate in cell cycle regulation, a significant proportion interacts with chromatin to modulate, for instance, the transcription (i.e.: transcription factors) and the chromatin structure (i.e.: histones, chromatin remodeling complexes, condensin) These proteins can bind to chromatin by recognition to a specific DNA consensus sequence via different DNA-binding domains. Our findings expose for the first time that TRIP12 protein expression is tightly regulated during cell cycle, and, that TRIP12 interacts with euchromatin through a new functional N-terminal domain. By means of this chromatin interaction, we further propose that TRIP12 participates in mitotic entry by controlling duration of DNA replication. We further demonstrate that TRIP12 is implicated in mitotic progression and in chromosome stability

Methods

Results

Conclusion