A pathway leading to activation of BRCA1

Fanconi anaemia is a rare inherited disorder that causes children to develop bone marrow failure. Although a bone marrow transplant can cure the anaemia, many patients go on to develop a variety of cancers.The disorder is brought about by a mutation in any one of seven genes — five of which have been cloned. The proteins produced by these five genes form an enzyme that activates the sixth gene. Research teams led by Alan D'Andrea, of the Dana-Farber Cancer Institute in Boston, and Markus G

By | February 16, 2001

Fanconi anaemia is a rare inherited disorder that causes children to develop bone marrow failure. Although a bone marrow transplant can cure the anaemia, many patients go on to develop a variety of cancers.

The disorder is brought about by a mutation in any one of seven genes — five of which have been cloned. The proteins produced by these five genes form an enzyme that activates the sixth gene. Research teams led by Alan D'Andrea, of the Dana-Farber Cancer Institute in Boston, and Markus Grompe, of the Oregon Health Sciences University in Portland, report in the 16 February Molecular Cell that they have cloned and identified that sixth gene, called FANCD2 (Mol Cell 2001, 7: 241-248). In a second the group also reports that FANCD2 produces a protein that switches on BRCA1 (Mol Cell 2001, 7: 249-262).

Approximately 50% of women with a strong family history of breast cancer have a defective BRCA1 gene. The protein encoded by BRCA1 helps repair damaged DNA, but little was known until now about how BRCA1 is activated. It seems that the FANCD2 protein becomes monoubiquitinated in response to DNA damage. The ubiquitination serves as a targeting signal that enables FANCD2 to interact with BRCA1. Once bound, the two proteins co-operate in DNA repair.

D'Andrea believes that it may be possible to design a drug that amplifies the effects of FANCD2, thus accelerating the repair work of BRCA1 and reducing the chances that breast cancer will occur in people with a genetic predisposition for it. But, says D'Andrea, "Much work remains to be done before such therapies become a reality."

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