Scientists are beginning to unravel the complex cellular events that comprise this rare disorder, and in doing so are acquiring information that may be useful for understanding common forms of cancer.

A paper published in today's issue of Cell describes a discovery that explains part of the cellular basis of FA, and that makes an interesting molecular link to a clinically distinct genetic disease, ataxia telangiectasia (AT).

One characteristic of FA is that cells exhibit hypersensitivity to chemicals that damage DNA. Sensitivity to such chemicals usually indicates a defect in DNA repair mechanisms.

It was previously shown that chemical-induced DNA damage results in a physical modification (ubiquitination) of FANCD2, one of the set of proteins that can be defective in patients with FA.

Some FA subtypes also exhibit an increased sensitivity to DNA damage induced by ionizing radiation. A similar sensitivity to ionizing radiation occurs in other human syndromes, including AT, which is caused by mutations in the ATM gene. As in FA, people with AT also face a high risk of developing cancer.

Researchers at Harvard Medical School led by Dr. Alan D'Andrea now report that FANCD2 serves as a link between the chemical- and ionizing radiation-induced DNA damage response pathways.

They have found that FANCD2 is subject to different modifications depending upon the nature of the DNA-damaging agent.

When normal cells are irradiated, a phosphate group is added to the FANCD2 protein, and this modification targets FANCD2 to stimulate a DNA repair pathway separate from that used to respond to chemical-induced damage. Interestingly, the ATM gene encodes the protein that adds the phosphate group to FANCD2. This discovery explains the common sensitivity to radiation shared by these distinct genetic disorders.

The authors propose that FANCD2 functions as a kind of molecular switch, and that depending on the modification it receives, it activates the different DNA repair pathways.

There is also evidence that the genes involved in FA play a role in cancers other than leukemia.

“Although FA and AT are rare diseases, recent studies have shown that breast cancer and other commonly occurring tumors are caused by acquired defects in these DNA repair pathways,” explains Dr. D'Andrea.


[Contact: Dr. Alan D. D'Andrea]

17-May-2002