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Tim
J. Yen Ph.D.
Senior Member, Fox Chase Cancer Center
Adjunct Associate Professor, Dept of Genetics
Cell
Biology and Physiology Program
Address
Fox Chase Cancer Center
7701 Burholme Ave
Philadelphia, PA 19111
Office tel.: 215 728-2590
Lab tel.: 215 728-4311
Fax: 215 728-2412
E-mail: tj_yen@fccc.edu
Link(s)
Dr. Yen's
Fox Chase Cancer Center page
Dr. Yen's
Lab page
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RESEARCH
INTERESTS
- We are interested in understanding the structure and function
of kinetochores as a means to elucidate mechanisms of chromosome
alignment and mitotic checkpoint control.
Key
words: Mitosis, Cancer, Chromosomes,
Checkpoints.
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DESCRIPTION
OF RESEARCH
Growth of multicellular organisms is critically dependent
on the ability of individual cells to duplicate and separate
their genomes during cell division. Defects in DNA replication
and chromosome segregation can lead to significant human health
problems that include cancer, birth defects and infertility.
The mechanisms that are responsible for replicating the genome
and to segregate the resultant chromosomes during mitosis
can be viewed as mechanical events because the proteins involved
in these functions are molecular machines. Superimposed on
the mechanical processes are regulatory mechanisms called
checkpoints that monitor the molecular machines to ensure
that their tasks are accomplished accurately and in a timely
manner. Thus, checkpoints play an essential role in maintaining
genome stability by ensuring that errors in DNA replication
and chromosome segregation are corrected before cells are
allowed to divide.
Our laboratory is focused on understanding the mechanical
and regulatory mechanisms that ensure that chromosomes are
properly attached and segregated by the spindle during mitosis.
We have focused our attention on characterizing the molecular
composition and function of the kinetochore, as this is the
structure on the chromosome that establishes and monitors
connections with microtubules. We have identified molecular
motors and checkpoint proteins that reside at kinetochores
and are interested in understanding how these proteins interact
with each other to carry out complex kinetochore functions.
Our research is particularly relevant to cancer research as
drugs that inhibit mitosis are a major modality for anti-cancer
therapy. Current drugs however, lack specificity as they target
microtubules that provide functions that not only are critical
for mitosis but also for other essential cellular processes
such as vesicle transport, cell shape and locomotion. Our
studies of how chromosomes segregate have revealed novel proteins
that provide functions that are critical only during mitosis.
As such, these proteins should be ideal candidates for the
development of highly specific anti-mitotic drugs.
RECENT
PUBLICATIONS
Daniel, R., Kao, G., Taganov, K., Greger, J., Favorova, O.,
Merkel, G., Yen, T.J., Katz, R.A., Skalka, A.M. Evidence that
the retroviral DNA integration process triggers an ATR-dependent
DNA damage response. Proc. Natl. Acad. Sci. U.S.A.
100:4778-4783, 2003.
Fletcher L, Yen TJ, Muschel RJ. Related Articles, Links Abstract
DNA damage in HeLa cells induced arrest at a discrete point
in G2 phase as defined by CENP-F localization. Radiat
Res. 159:604-11, 2003.
Kao, G.D., McKenna, W.G., Guenther, M.G., Muschel, R.J.,
Lazar, M.A., Yen,T.J. Histone Deacetylase 4 interacts with
53BP1 to mediate the DNA damage response. J.Cell Biol.
160:1017-1027, 2003.
Liu, S.T., Hittle, J.C., Jablonski, S.A., Campbell, M.S.,
Yoda, K., Yen, T.J. Human CENP-I specifies localization of
CENP-F, MAD1 and MAD2 to kinetochores and is essential for
mitosis. Nat. Cell Biol. 5:341-345, 2003.
Liu, S.T., Hittle, J.C., Lees, E., Yen, T.J., Human MPS1
kinase is required for mitotic arrest induced by the loss
of CENP-E from kinetochores. Mol. Biol. Cell. 14:
1638-1651, 2003.
Lab
ROTATION
PROJECTS FOR 2006-2007
Dividing cells rely on three basic mechanisms to maintain
genome stability. Two of these mechanisms, duplication of
the genome by DNA replication and the segregation of each
genome copy into dividing cells during mitosis, are mechanical
in nature. These two bioengineering tasks require a large
number of structural proteins that function together as complex
machines. Superimposed on these two mechanical systems is
a third component of quality control that monitors the integrity
of the genome to ensure its accurate replication and distribution.
Defects in any one of these three fundamental cellular processes
lead to the accumulation of mutations in the genome that result
in cell death or uncontrolled cell growth. An understanding
of the biochemical basis of the three mechanisms that maintain
genome stability is of utmost importance in developing new
methods of cancer detection and treatment.
Our laboratory is focused on studying two of the three essential
processes that involve:
- Studying the biomechanical events that segregate chromosomes
between two daughter cells during mitosis
- Characterizing the mechanism of the mitotic checkpoint
to prevent aneuploidy
- Studying a checkpoint system to monitor radiation-induced
DNA damage.
- Lab
personnel:
- Sandra Jablonski, Ph.D. - Staff Scientist
Valery Sudakin, Ph.D. - Research Associate
Song-Tao Liu, Ph.D. - Postdoctoral Fellow
Nadia Ladygina, Graduate Student
James Hittle, B.S. - Technical Specialist
Beatrice J. Conner - Scientific Technician
Nadia Tikhmyanova, M.A. - Scientific Technician
Dina Matheos, Ph.D - Postdoctoral Fellow
Jie Feng, Ph.D. - Postdoctoral Fellow
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last updated 9/2003
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