Ali Hamiche

Fellowship 2015

ARCHIVE

After receiving my B.S. degree in Biochemistry from the University of Orsay (PARIS XI) in 1991, I spent the next five years in Dr. Ariel Prunell lab at the University of Paris 6, studying the structure of the nucleosome using biophysical and biochemical methods, and received my Ph.D. in Molecular and Cell Biology in 1995. I was hired in 1996 by the CNRS as a junior Staff Scientist in Helene Richard-Foy lab (Toulouse, France) where I started working on the role of chromatin structure in gene regulation. I continued to focus on chromatin research and enjoyed a 2 years (1998-2000) postdoctoral training with Dr. Carl Wu at NIH, where I discovered the mechanism of chromatin remodeling by the Drosophila NURF complex. I joined in 2003 Annick Harell Bellan Lab at the Andre Lwoff Institute in Villejuif (Paris) where I started developing proteomic techniques to analyze the role of the histone variant macroH2A in gene regulation. In 2008, I was hired as a group leader at IGBMC (Strasbourg, France) where I hold now a CNRS Director of Research position. My research is devoted to understanding the role of histone variants in epigenetic regulations and tumorigenesis. I have worked extensively on the isolation and purification of histone variant complexes and have studied their role by using the state of the art molecular and cell biology techniques. Among others, I have isolated and characterized the histone variant CENP-A deposition machineries and identified DAXX as a novel histone chaperone responsible for the replication-independent deposition of H3.3. More recently, I have identified ANP32E as a histone chaperone that removes H2AZ from promoters and provided the molecular basis for H2A.Z recognition and H2A.Z/H2B nucleosomal eviction by ANP32E. My work is funded by different French agencies. My team was rated A+ in the evaluation carried out by the AERES committee in 2008 and 2012. My group was recently recognized as an outstanding research group (Equipe labelisée) by the National Ligue against Cancer and awarded a five years grant (2014-2019). Recently, I received the prestigious Dandrimont-Bénicourt price from the French Academia of Sciences for my contribution to the epigenetic field and oncogenesis.

Mechanisms of CENP-A assembly and Propagation at Centromeres

The centromere is a specialized region localized at the site of primary constriction of the chromosome in eukaryotic cells. The centromere is of vital importance for genetic stability, and defects in centromere structure result in chromosome mis-segregation, aneuploidy and cancer. Because the DNA sequence of centromeres is not conserved, it is widely accepted that a protein, termed CENP-A (centromere protein-A) is the epigenetic marker of the centromeres. CENP-A is a specialized histone variant which replaces conventional histone H3 at the centromere. Incorporation of CENP-A confers novel structural and functional properties to the nucleosome for which the molecular basis is not known.

In this proposal, we will focus on the structure and function of CENPA in kinetochore assembly and centromere activity, and we will study in detail the role of this histone variant in developing human diseases such as cancer. We propose to study how CENP-A, the key epigenetic player in centromere organization and identity, is deposited to the centromere and which are the factors involved in this process. We will identify such new factors and analyze how they function in a series of in vivo and in vitro experiments. Our preliminary data suggests that a novel kinase is implicated in CENP-A deposition and novel experiments aiming at understanding its function are in progress. Ablation of this kinase leads to CENP-A mislocalization and chromosome mis-segregation. We will use super-resolution light microscopy (ground-state depletion, GSD, related with STORM) to study the mechanism of CENP-A deposition by its chaperone HJURP. We will combine super-resolution light microscopy and advanced high-resolution single particle cryo electron microscopy (cryo-EM) to study the 3D architecture of CENP-A chromatin and associated complexes. The expected data will reveal how a plethora of crucial epigenetic factors function in maintaining genomic stability. Shedding light on the CENP-A functions is of crucial importance for understanding the mechanism of active kinetochore assembly and thus, the epigenetic origins of chromosome instability in diseases.