Rare Genetic Diseases Share Molecular Switch

A new study explains part of the cellular basis of Fanconi anemia (FA) and also establishes a molecular link to a clinically distinct genetic disease, ataxia telangiectasia (AT). Fanconi anemia (FA) is an inherited genetic disorder characterized by birth defects, progressive bone marrow failure, and an extremely high risk of developing leukemia or other forms of cancer. The study was published in the May 17, 2002, issue of Cell.

Cells from individuals with FA are hypersensitive to chemicals that damage DNA, indicating a defect in DNA repair mechanisms. Some FA subtypes also exhibit an increased sensitivity to DNA damage induced by ionizing radiation. This type of sensitivity is also found in other human syndromes including AT.

It was known that chemically induced damage to DNA modifies the Fanconi anemia protein, FANCD2, in different ways, depending on the nature of the DNA-damaging agent. Researchers at Harvard Medical School (Boston MA, USA) 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.

Exposure of normal cells to ionizing radiation causes phosphorylation of the FANCD2 protein that is mediated by the product of the ATM gene (the gene responsible for phosphorylation in AT). This modification induces FANCD2 to stimulate a DNA repair pathway separate from that used to respond to chemical-induced damage. 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 different DNA repair pathways. "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.



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