IGBMC | Team PAPAI-BEN SHEM ( Transcription co-activators), Illkirch, France
Supervisors: Dr. Changqing Li, Dr. Adam Ben-Shem & Dr. Gabor Papai
Background
The TIP60/EP400 complex (TIP60-C) is a highly conserved 20-subunit chromatin remodeling complex that plays fundamental roles in gene transcription and the maintenance of genome integrity. Through its lysine acetyltransferase (KAT) activity, TIP60-C acetylates histones H4 and H2A to promote chromatin relaxation, while its EP400 ATPase subunit catalyzes the exchange of canonical H2A for the histone variant H2A.Z, thereby regulating chromatin dynamics during transcription and DNA damage repair.
Beyond chromatin regulation, TIP60-C acts as a central signaling hub that coordinates diverse cellular processes, including DNA repair, immune responses, cell cycle progression, apoptosis, autophagy, metabolism, and development. These functions are mediated through the acetylation of both histone and non-histone substrates, which modulates protein activity, stability, and molecular interactions. Dysregulation of TIP60-C is implicated in numerous human diseases, including cancer, neurodegenerative disorders, and viral infections, making it a compelling therapeutic target.
Our laboratory recently solved the high-resolution cryo-EM structure of the endogenous human TIP60 complex (https://www.nature.com/articles/s41586-024-08011-w), providing an unprecedented view of its molecular architecture. This PhD position builds directly on that breakthrough.
Project Aims
1. Determine how TIP60-C recognizes nucleosomes to drive H2A.Z exchange.
2. Elucidate the molecular mechanisms by which TIP60-C promotes DNA damage repair.
3. Identify and develop novel therapeutic modulators of TIP60-C.
Approach
The project integrates structural biology, biochemistry, cell biology, and computational drug discovery. The successful candidate will employ an interdisciplinary approach, combining single-particle cryo-electron microscopy, structure-based virtual screening, AI-driven de novo peptide and mini-protein design, biochemical characterization, and cellular functional assays.
Candidate Profile
Expected start date: 1 December 2026.
What We Offer
Application
Interested candidates should send a CV, a brief statement of research interests, Grades obtained during the Licence and Master studies, and contact details for two references to lic@igbmc.fr before 30 September, 2026.