Genes Identified that Cause Genomic Instability

Cancer researchers working with a mouse model have found that the removal of the genes H2AX and P53 results in genetically unstable cells prone to give rise to lymphomas and solid tumors.

The H2AXT gene codes for a histone variant phosphorylated in chromatin surrounding DNA double-strand breaks. The P53 gene produces a molecular sentinel protein that suppresses proliferation of cells with damaged DNA.

Investigators at Harvard Medical School (Boston, MA, USA; www.harvard.edu) created a line of "double knockout” mice lacking both the H2AX and P53 genes. They found that these animals demonstrated a dramatically increased rate of tumors appearing beyond what would be seen with H2AX deficiency alone and far beyond p53 deficiency alone.

A second line of mice was developed that lacked only one of the two copies of the H2AX gene. "Both surprising and potentially very significant for human cancers was that p53-deficient mice with deletion of one of their two copies of the H2AX gene came down with cancer much earlier,” said senior author Dr. Fredrick W. Alt, professor of pediatrics and genetics at Harvard Medical School. "They showed a very broad spectrum of tumors that was somewhat different than p53-deficient animals missing both H2AX genes.”

The H2AX gene is located in a region of chromosome 11, which is known to be altered in many human tumors. The authors concluded their paper in the August 8, 2003, issue of Cell by saying that genes in that region will very likely prove to be major players in cancer-causing genomic instability.



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