A role for monoubiquitinated FANCD2 at telomeres

Both Fanconi anemia (FA) and telomere dysfunction are associated with chromosome instability and an increased risk of cancer. Because of these similari-ties, we have investigated whether there is a rela-tionship between the FA protein, FANCD2 and telomeres. We find that FANCD2 nuclear foci colo-calize with telomeres and PML bodies in immorta-lized telomerase-negative cells. These cells maintain telomeres by alternative lengthening of tel-omeres (ALT). In contrast, FANCD2 does not colo-calize with telomeres or PML bodies in cells which express telomerase. Using a siRNA approach we find that FANCA and FANCL, which are components of the FA nuclear core complex, regulate FANCD2 monoubiquitination and the telomeric localization of FANCD2 in ALT cells. Transient depletion of FANCD2, or FANCA, results in a dramatic loss of detectable telomeres in ALT cells but not in telomer-ase-expressing cells. Furthermore, telomere loss following depletion of these proteins in ALT cells is associated with decreased homologous recombi-nation between telomeres (T-SCE). Thus, the FA pathway has a novel function in ALT telomere main-tenance related to DNA repair. ALT telomere main-tenance is therefore one mechanism by which monoubiquitinated FANCD2 may promote genetic stability