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Overview of our research and its relevance to human cancer
1.  Epigenetics and Genome Stability

Our laboratory studies the relationship between the genome and the cell nucleus.  We are particularly interested in how "higher-order" organization impacts upon the regulation of the genome and the processes that act upon it.  One of the striking aspects of human cancers is that they are accompanied by changes in nuclear and chromatin structure.  These changes can often be used by pathologists to stage the cancer and predict its aggressiveness.  Breast and prostate cancers are examples where these correlations have proven to be particularly valuable in the clinic.  One of the major objectives of our research program is to better understand the relationship between nuclear and chromatin morphology and cell behaviour.  This will lead to a better understanding of the fundamental rules of genome regulation in human cancers and reveal novel opportunities/mechanisms for therapeutic intervention and improved treatment of human cancers.    

About the Principal Investigator


B.Sc. 1986-Brandon University

Ph.D. 1993-Biochemistry and Molecular Biology, University of Manitoba

Postdoctoral-1993-1998 Department of Medical Biochemistry, University of Calgary


CIHR New Investigator 2000-2005

AHFMR Scholar 2001-2006
AHFMR Senior Scholar 2006-present
Current Research Support: CIHR, NCIC, ACB


Dr. Michael J Hendzel, Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada

phone: 780-432-8439

fax:  780-432-8892

e-mail:  michaelh@cancerboard.ab.ca


Our research has focused upon the relationship between the posttranslational modification of histones and the regulation of chromatin structure and function throughout the cell cycle.  By employing quantitative methodology in fluorescence microscopy (widefield, deconvolution, laser scanning confocal), we have been particularly interested in changes in histone posttranslational modifications that accompany chromosome condensation during entry into mitosis and chromatin decondensation during exit from mitosis.  Our current focus is on characterizing the function of the increase in histone H3 lysine 9 trimethylation as cells enter mitosis and the decrease in histone H3 lysine 9 trimethylation as cells exit mitosis (McManus et al. 2006).  The absence of this methylation is associated with defects in chromosome segregation that could contribute to cancer initiation and progression as well as provide a target that can be used to kill cancer cells.  In this effort, we are collaborating with Dr. Gordon Chan on the contribution of histone H3 lysine 9 trimethylation to kinetochore assembly and function, Dr. Robert Campbell to develop drugs that inhibit this methylation and to develop affinity probes that may be used to alter the function of this methylation and/or to quantify this methylation in human cancer specimens, Dr. Alan Underhill to define the importance of this methylation in differentiation-associated changes in gene expression.  In the long term, we hope to be able to exploit what we learn about this methylation event into cancer screening and cancer therapeutics.

 Recent Publications:

McManus, K.J., V.L. Biron, R. Heit, D.A. Underhill, and M.J. Hendzel. 2006. Dynamic Changes in Histone H3 Lysine 9 Methylations: IDENTIFICATION OF A MITOSIS-SPECIFIC FUNCTION FOR DYNAMIC METHYLATION IN CHROMOSOME CONGRESSION AND SEGREGATION. J Biol Chem. 281:8888-97.

McManus, K.J., and M.J. Hendzel. 2005a. ATM-dependent DNA damage-independent mitotic phosphorylation of H2AX in normally growing mammalian cells. Mol Biol Cell. 16:5013-25.

2.  Dynamic Processes inside the Cell Nucleus

The cell nucleus is not a homogeneous structure.  Rather, proteins, DNA, and RNA are ordered within the nucleus based upon functional relationships.  The changes in nuclear organization that are common in human cancers reflects the intimate relationship between function and organization within the cell nucleus.  Nonetheless, the rules that govern this organization and how it impacts upon the regulation of the genome and the phenotype of the cell are only beginning to be defined.  We have been using quantitative live cell microscopy techniques including fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS), and 3-D timelapse microscopy to define the relationship between the organization and functions of the cell nucleus.  The knowledge gained from these studies will help us interpret the biochemical and phenotypic changes in cancer cells based upon the changes in cancer cell organization and is an important step towards rationally designed cancer therapy.  Most recently, we have used these methods to identify and characterize a dynamic equilibrium between monomeric and polymeric forms of actin within the nucleoplasm.  A commentary describing the significance of this finding in our understanding of how processes occur within the cell nucleus can be found here.  Our previous work has shown that, while compartments and chromatin organizations are relatively stable, the molecular constituents of these structures are constantly exchanging between bound or functionally engaged forms of proteins and freely diffusing nucleoplasmic forms.  A commentary highlighting the contribution of our studies on splicing factor dynamics to our understanding of nuclear organization and function can be found here.  Our overall objective is to determine the contributions of the physical microenvironment to the orchestration of nuclear functions. 
Recent Publications:

McDonald, D., G. Carrero, C. Andrin, G. de Vries, and M.J. Hendzel. 2006. Nucleoplasmic beta-actin exists in a dynamic equilibrium between low-mobility polymeric species and rapidly diffusing populations. J Cell Biol. 172:541-52.

Carrero, G., M.J. Hendzel, and G. de Vries. 2006. Modelling the compartmentalization of splicing factors. J Theor Biol. 239:298-312.

3.  DNA Damage and DNA Damage Repair

Radiation therapy and several chemotherapeutic agents kill cancer cells by introducing double strand breaks into the DNA.  It follows that the effectiveness of these therapies can be enhanced through mechanisms that facilitate the generation of damage that cannot be repaired or through mechanisms where the machinery that repairs double-strand breaks within the cell is inhibited.  We are collaborating with Dr. Joan Turner to determine whether or not modulating the structure of chromatin can alter the radiosensitivity of cells.  In these studies, which are currently aimed at improving breast cancer radiotherapy, we are trying to increase the complexity of the damage by inducing chromatin condensation.  More complex lesions are thought to be more difficult/impossible to repair.  Many human cancers, including some of the most aggressive forms of breast cancer, have less condensed chromatin than their normal counterparts.  Consequently, if the radiosensitivity of cells can be increased using drugs that facilitate chromatin condensation, such an approach should increase the radiosensitivity of the cancer without increasing the radiosensitivity of the surrounding normal tissue.  Conversely, normal tissue damage often limits radiotherapy, thereby reducing the probability of curing patients with radiation.  Drugs that decrease chromatin condensation may be used to decrease normal tissue damage--again increasing the ability to deliver curative radiotherapy. 

We also collaborate with Dr. Guy Poirier and Dr. Jean-Yves Masson to characterize the cellular mechanisms responsible for sensing and signaling the existence of double-strand breaks.  One of the objectives of this research is to characterize the specific role of poly(ADP-ribosyl)ation in double-strand break repair.  Inhibitors of this posttranslational modification have recently been shown to be selectively toxic to cells with BRCA mutations. 

Our independent work on DNA repair has the objective of defining the function of nuclear actin in the DNA double-strand break repair process.  We have evidence for direct interactions between DNA repair machinery and polymeric forms of actin, which we recently showed were present within the interphase nucleus.  We have also determined that inhibiting actin polymerization inhibits the repair of DNA double-strand breaks.  There are multiple opportunities to improve upon existing cancer therapies from the information that we will gather from these studies.  First, actin polymerization is targeted during cellular transformation and must be remodelled at each stage of cancer progression.  Understanding the interaction between the regulation of actin polymerization and the efficiency of DNA double-strand break repair could lead to better prognostic indicators of how patients will respond to radiotherapy.  In addition, identifying the specific interactions between actin and the DNA double-strand break repair therapy will provide a list of new therapeutic targets to exploit in order to improve the effectiveness of radiotherapy in patients. 


Recent Publications

Gagne, J.P., M.J. Hendzel, A. Droit, and G.G. Poirier. 2006. The expanding role of poly(ADP-ribose) metabolism: current challenges and new perspectives. Curr Opin Cell Biol. 18:145-51.

Haince, J.F., M.E. Ouellet, D. McDonald, M.J. Hendzel, and G.G. Poirier. 2006. Dynamic relocation of poly(ADP-ribose) glycohydrolase isoforms during radiation-induced DNA damage. Biochim Biophys Acta. 1763:226-37.

Haince, J.F., M. Rouleau, M.J. Hendzel, J.Y. Masson, and G.G. Poirier. 2005. Targeting poly(ADP-ribosyl)ation: a promising approach in cancer therapy. Trends Mol Med. 11:456-63.

Han, J., M.J. Hendzel, and J. Allalunis-Turner. 2006. Quantitative analysis reveals asynchronous and more than DSB-associated histone H2AX phosphorylation after exposure to ionizing radiation. Radiat Res. 165:283-92.

Rodrigue, A., M. Lafrance, M.C. Gauthier, D. McDonald, M. Hendzel, S.C. West, M. Jasin, and J.Y. Masson. 2006. Interplay between human DNA repair proteins at a unique double-strand break in vivo. Embo J. 25:222-31.