Cincinnati—In the November 5 issue of Science,
Yolanda Sanchez, PhD, assistant professor of molecular genetics at the
University of Cincinnati (UC) College of Medicine, coauthored an
article detailing the findings of research on how cells repair DNA. DNA
carries information for the body, such as height, hair and eye color,
and the position of the organs. It is critical that the information in
the genetic code is copied accurately before the cell divides. Exposure
to certain mutagenic agents in the environment can alter or damage the
DNA. If the damaged DNA is not repaired before replication, it can lead
to changes or mistakes in the code. The mutation is then copied and
perpetuated in the genetic code of all descendants from that cell. The
damage can also lead to broken chromosomes that would result in cells
with too much or too little genetic information after division.
example, when people decide to get a tan, their DNA is constantly under
attack by the sun's ultraviolet rays. Depending upon the nature and
severity of the damage from ultraviolet light, these mutations may
result in dangerous changes in the cellular proteins that regulate cell
division. Uncontrolled cell division then becomes cancer and can also
cause cell death.
Sanchez conducted this research with
postdoctoral fellow Jeff Bachant, PhD, while working in the laboratory
of principal researcher Stephen J. Elledge, PhD, professor in the
Department of Biochemistry, Howard Hughes Medical Institute (HHMI),
Baylor College of Medicine in Houston. Following her arrival at UC,
Sanchez and UC research assistant Dawn Honican continued to work on
this question along with the authors at HHMI in Houston.
prevent mutations that lead to uncontrolled growth, cells have special
"quality controlling" proteins that include dedicated scouts that look
for damage to the DNA. When damaged DNA is detected, the scouts signal
"messenger" proteins, which place the cell on alert. When the alert is
given, cell division is stopped, and the "repair crew" is called. The
"scout" and "messenger" proteins and the responses they regulate are
part of what is called the checkpoint pathways. Once the damage is
repaired, the cell is permitted to resume making a copy of the genetic
information and proceed with cell division.
previously identified these "scout" proteins that signal the presence
of DNA damage and delay cell division, in order to allow time to repair
the damage to the DNA. In their current paper, the same team of
researchers describe the mechanism used by the signaling proteins which
prevent the separation of chromosomes during mitosis to daughter cells.
This inhibiting action occurs when damaged DNA has been detected. The
task of preventing mitosis is shared between two proteins Chk1 and
Rad53, which prevent chromosome separation (anaphase) and entry into
the next cell cycle, respectively.
According to Sanchez, "Our
understanding of the circuitry of the checkpoint pathways that regulate
this response may allow us to design more effective cancer treatments."
Most cancer cells are partially compromised in their ability to respond
to DNA damage, which limits the effectiveness of current cancer
treatments that involve the use of DNA-damaging agents such as
chemotherapy and radiation. This new research may lead to treatments in
which cancer cells are rendered more sensitive to chemotherapy or
radiation treatment through inactivation of an additional branch of the
checkpoint. Simultaneously, the normal cells would retain one branch of
the checkpoint to allow them to monitor damaged DNA, stop replication,
and repair DNA. "In this way, the chemotherapy would be more effective
in killing the cancer, with less toxic side effects to the cancer
patient," says Sanchez.
Additional coauthors were: Hong Wang,
Fenghua Hu, Dou Liu, and Michael Tetzlaff of the HHMI at the Baylor
College of Medicine in Houston. Most of the research was conducted in
the laboratory of principal investigator Stephen J. Elledge, PhD,
professor at the Department of Biochemistry, HHMI, Baylor College of
Medicine in Houston.