Deadly Network: Disease-causing protein links two DNA damage disorders (DNA repair)
Authors: Davenport R. John 
Published: August 2003

Previously unconnected molecular pathways for two rare human diseases now appear to converge on a single protein, according to research presented at the American Society for Cell Biology Annual Meeting, which was held 8 to 12 December in Washington, D.C. The results suggest that human diseases that confer high cancer susceptibility due to DNA damage might share mechanisms in addition to symptoms.

Patients--predominantly young children--with the unusual inherited disease Fanconi anemia (FA) suffer from an increased risk of cancer, especially types that normally affect only elderly adults. The behavior of cells from FA patients suggests that defects in the ability to repair DNA are to blame. When grown in culture, the cells succumb to DNA-damaging treatments with agents such as mitomycin C and radiation that normal cells can endure; in addition, their chromosomes break, increasing the likelihood of genetic rearrangements that cause cancer. Genetic studies have pinpointed mutations in six genes that lead to the disorder. Five of the genes encode proteins that normally act in concert to activate the protein product of the sixth gene, called FANCD2, by tacking a protein called ubiquitin onto it. The addition of many ubiquitin molecules usually targets proteins for the garbage heap, but appending a single ubiquitin prods FANCD2 into action, sending it to chromosome locations that are likely sites of mitomycin C-induced DNA damage. FANCD2 thwarts the lethal effects of radiation as well, but the ubiquitin alteration doesn't govern that ability, and scientists are eager to find out what does.

Radiation also brings down cells carrying mutations that cause ataxia-telangiectasia (AT), a degenerative disease characterized by premature cancers and weakened immunity. Because of this similarity, D'Andrea and colleagues wondered whether the molecular pathways of AT and FA might interweave. The gene responsible for AT, called

ATM

(see Transgenic Mouse Entries:
atm strain 1
,
atm strain 2
, and
atm strain 3
), encodes a protein that sets radiation damage repair mechanisms into motion by tacking phosphate groups onto other proteins, so the researchers probed whether it might perform the same reaction on FANCD2. FANCD2 isolated from irradiated cells carries a phosphate group not found on protein from untreated cells, according to the new work--and ATM is required to produce this modified form of FANCD2. In contrast, FANCD2 in mitomycin C-treated cells does not bear the phosphate mark. Perhaps, D'Andrea and colleagues suggest, ATM glues a phosphate onto FANCD2 in response to irradiation.

Together, these results suggest that mitomycin C and radiation instigate the addition of a ubiquitin and a phosphate, respectively, to FANCD2; the two forms of FANCD2 then activate separate response pathways to repair the damage. Additional experiments support this idea. The group created two alternative forms of FANCD2: One--called S222A--lacks the site necessary for phosphate attachment, and another--called K561R--rejects the ubiquitin group. Cells that carry S222A perish when treated with radiation but not when bathed in mitomycin C. And cells with K561R yield to mitomycin C but recover from radiation.

AT and FA patients exhibit similar symptoms, and the new results hint that the two diseases might share an aberrant radiation damage repair pathway as well. Many pieces of the puzzle still need to be filled in: The molecular targets of FANCD2 remain mysterious, and it is unclear how the addition of either ubiquitin or phosphate alters FANCD2 function. Fleshing out the pathways that underlie AT and FA might reveal machinations of other disorders associated with DNA damage and high cancer risk, including Werner syndrome and other premature aging afflictions. Furthermore, details about the deadly AT-FA connection could lay the groundwork for possible treatments for these rare diseases and also could uncover mechanisms that cause cancer in the rest of the population.

--R. John Davenport

Further Reading

• Fanconi Anemia Mutation Database
http://www.rockefeller.edu/fanconi/mutate

• Fanconi Anemia Research Fund
http://www.fanconi.org

• A. D. D'Andrea, I. Garcia-Higuera, W. S. Lane, B. Xu, M. B. Kastan, T. Taniguchi, Differential activation of the Fanconi anemia protein, FANCD2, by monoubiquitination and phosphorylation. American Society for Cell Biology Annual Meeting, 8 to 12 December 2001, Washington, D.C.
http://www.ascb.org/meetings/am2001/main01mtg.htm