Newly Identified Tumor Suppressor Cooperates With P53 To Protect Mice Against Tumors

"This work demonstrates that H2AX plays an important role in maintaining the integrity of cells' genetic information, and therefore in preventing tumor formation," said Andre Nussenzweig, Ph.D., of NCI's Experimental Immunology Branch, the lead researcher on the study. "Both copies of the H2AX gene are required for optimal protection against tumors."

The work by the NCI research team is in agreement with a similar study led by Fred Alt, Ph.D., at Harvard University, published in the same issue of Cell**, which also demonstrates that H2AX cooperates with p53 to ensure that damaged cells do not grow out of control and promote tumor development.

The protein produced by the H2AX gene belongs to a class of molecules known as histones, which are involved in the packaging of DNA inside the cell. About five years ago, scientists first recognized that the H2AX histone is involved in the cell's response to DNA damage — a discovery made by William Bonner, Ph.D., at NCI.

H2AX is activated when DNA molecules inside the cell are broken. Such breakage can be caused by external factors such as radiation, but also routinely occurs during normal cellular processes. Although breaks in DNA are necessary for some biological processes, it is essential that the breaks be repaired. If breaks remain when a cell divides, important genetic information located on the DNA molecules can be lost in some cells while other cells receive extra copies of certain genes.

One potential consequence of a loss or gain of genetic information is the development of cells whose growth is not properly regulated. Uncontrolled multiplication of these cells, in turn, can give rise to cancer. Because of its role in the repair of broken DNA molecules, H2AX helps maintain genomic integrity; for this reason, the NCI researchers speculated that mice without H2AX might develop more tumors than those with H2AX.

The researchers studied mice in which they had eliminated one or both of the two normal copies of the H2AX gene. They discovered that DNA in the cells of mice lacking H2AX was frequently broken and rearranged. If this type of damage occurred in regions of DNA critical for growth control, tumor formation could result. Surprisingly, however, mice lacking H2AX developed no tumors during the course of the experiment.

Nussenzweig and colleagues speculated that the lack of tumors in mice without H2AX was due to the activity of a protein known as p53, which prevents cells containing damaged DNA from dividing until the damage has been repaired, or, in the case of severe damage, causes cells to die. In this way, p53 ensures that cells do not pass on damaged DNA to new cells, and helps reduce the potential cancer threat.

To test the idea that p53 protected the mice from tumors that might arise due to a lack of H2AX, the researchers eliminated one or both copies of the H2AX gene in mice that already lacked p53. They found that in these animals, partial or complete loss of H2AX led to increased tumor formation. Mice lacking p53 develop a high number of tumors. The additional loss of H2AX in these mice caused tumors to develop earlier and decreased the average lifespan. Animals completely lacking both genes lived an average of only 11.6 weeks, as compared to 23.4 weeks for those with no p53 but normal H2AX. These mice were particularly susceptible to lymphomas.

The effects of eliminating only one of the H2AX genes in mice with no p53 were intermediate. These mice lived for an average of 17 weeks, and developed a range of tumors including lymphomas, sarcomas, leukemia, and brain tumors. Thus, unlike "classical" tumor suppressors, in which loss of both copies of the gene is necessary for tumor development, partial loss of H2AX function predisposes mice to tumor formation.

The research team's findings in mice indicate that in the absence of p53, loss of just one copy of the H2AX gene is enough to cause genetic alterations and promote tumor formation, and are the first to demonstrate that a core histone component functions as a tumor suppressor. In many human tumors, the region of DNA that includes the H2AX gene is missing, suggesting that H2AX may play a similar role in protecting against the development of human cancers.

For more information about cancer, visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).