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
About the Principal
Ph.D. 1993-Biochemistry and
Molecular Biology, University of Manitoba
Department of Medical Biochemistry,
University of Calgary
CIHR New Investigator
AHFMR Scholar 2001-2006
AHFMR Senior Scholar
|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
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.
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.
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
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
overall objective is to determine the contributions of
the physical microenvironment to the orchestration of
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
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.
Damage and DNA Damage Repair
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
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.
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
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
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.