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University of Cincinnati Academic Health Center
Publish Date: 11/09/99
Media Contact: AHC Public Relations, (513) 558-4553
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Understanding How Cells Respond to DNA Damage May Lead to Better Cancer Treatments

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.

For 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.

To 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.

The researchers 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.

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