Researchers sifting through the indispensable machinery that senses and fixes broken DNA have discovered a new culprit that can induce instability in the genome and thereby set the stage for cancer to develop.

Studies in mice have shown that loss of H2AX, a gene that produces a protein called a histone that is part of the chromosomal structure, can tip the delicate balance of proteins that are curators of the human genome. When H2AX ceases to function properly, lymphomas and solid tumors can arise because errors in the genetic code are not always repaired correctly, according to the new research.

The finding may have important implications for understanding the origin of human cancers because a large number of human tumors are known to contain alterations in the region of chromosome 11 where the H2AX gene is located.

The research was reported in an article published in the journal Cell by Howard Hughes Medical Institute investigator Frederick Alt and colleagues at Children's Hospital in Boston and Harvard Medical School. Other co-authors are from the Tufts University School of Veterinary Medicine and Brigham and Women's Hospital.

According to Alt, previous studies by other researchers had shown that H2AX was activated when DNA breaks occur. DNA repair proteins fix genetic damage, but they are also called to action during the normal gene rearrangement that occurs in immune cells when they are readying to battle viruses and other threats.

What may be especially relevant to human cancers, said Alt, is that the H2AX gene is located in a region of chromosome 11 known to be altered in many human tumors. While there are other potential cancer-causing genes in that region, he said, the current evidence from the mouse model indicates that H2AX will very likely prove a major player in cancer-causing genomic instability.

Alt and his colleagues are now collaborating with scientists at the Dana-Farber Cancer Institute to analyze the status of H2AX genes in a wide range of human cancers. "We believe that the loss of H2AX could prove a major source of the rampant instability associated with the progression of a variety of different tumors," he said.

SOURCES:
Cell, August 8, 2003
Howard Hughes Medical Institute (http://www.hhmi.org)