Rare Birth Defect Linked to Cellular DNA Damage Response

January 15, 1999

By Lynn Yarris, lcyarris@lbl.gov

Berkeley Lab scientists have identified the cause of a rare but tragic birth defect as a deficiency in a protein that has also been linked to the ability of cells to respond to severe DNA damage.

Nijmegen Breakage Syndrome (NBS) is a genetic disorder in which babies who appear normal at birth fail to develop normal size skulls (microcephaly). In addition to having abnormally small heads, victims also suffer from low IQs, variable immune deficiencies, and an extremely high incidence of cancer.

James Carney and Bill Morgan, both of whom hold joint appointments with Berkeley Lab's Life Sciences Division and UC San Francisco, led a team of researchers who showed that the absence of a protein called "p95" is the cause of NBS. P95 is a member of a protein complex called "hMre11/hRad50," which is known to be involved in processing double-strand breaks in DNA.

Collaborating with Carney and Morgan on this research were John Petrini, Richard Maser and Heidi Olivares of the University of Wisconsin, Elizabeth Davis and Michelle LeBeau of the University of Chicago, and John Yates and Lara Hays of the University of Washington.

When Carney, Morgan and their colleagues isolated the gene that encodes for p95, they found it was identical to NBS1, a defective gene recently linked to the NBS disease. Because cells from NBS patients are susceptible to double-strand DNA breakage, this finding indicates that the role of p95 is to detect damaged DNA and signal for repairs.

"Without the presence of the p95 protein, damaged cells keep replicating as if they were undamaged," says Carney. "The result is NBS and possibly other problems as well."

The role played by p95's absence could be singled out, Carney explains, because the absence of any of the other proteins in the hMre11/ hRad50 complex is fatal to a cell.

Double-strand breakage of DNA's double helix is much more rare than the breakage of a single helical strand, but much more serious. Double-strand breakages lead to genomic instabilities, such as the chromosomal rearrangements or changes in chromosome numbers, which result in a cell's predisposition to malignancy.

Says Carney, "The implication of p95 and the hMre11/hRad50 protein complex in NBS constitutes an important link between DNA repair deficiencies and genomic instabilities associated with a predisposition to malignancy."

The next step, Carney says, will be to produce a 3-D image of p95. This will be accomplished, he says, through a combination of x-ray and electron-based protein crystallography at the Advanced Light Source and the National Center for Electron Microscopy, respectively.