A role for monoubiquitinated FANCD2 at telomeres in ALT cells.
Both Fanconi anemia (FA) and telomere dysfunction are associated with chromosome instability and an increased risk of cancer. Because of these similarities, we have investigated whether there is a relationship between the FA protein, FANCD2 and telomeres. We find that FANCD2 nuclear foci colocalize with telomeres and PML bodies in immortalized telomerase-negative cells. These cells maintain telomeres by alternative lengthening of telomeres (ALT). In contrast, FANCD2 does not colocalize 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 telomerase-expressing cells. Furthermore, telomere loss following depletion of these proteins in ALT cells is associated with decreased homologous recombination between telomeres (T-SCE). Thus, the FA pathway has a novel function in ALT telomere maintenance related to DNA repair. ALT telomere maintenance is therefore one mechanism by which monoubiquitinated FANCD2 may promote genetic stability.
Fan
Qiang
Q
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Zhang
Fan
F
Barrett
Briana
B
Ren
Keqin
K
Andreassen
Paul R
PR
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology; D002460:Cell Line; D002461:Cell Line, Transformed; D052217:Fanconi Anemia Complementation Group A Protein / Q000037:antagonists & inhibitors / Q000502:physiology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052240:Fanconi Anemia Complementation Group L Protein / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D012854:Sister Chromatid Exchange; D016615:Telomere / Q000737:chemistry / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000032:analysis; D054875:Ubiquitination
D018797:Cell Cycle Proteins; D052217:Fanconi Anemia Complementation Group A Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D035321:Telomeric Repeat Binding Protein 1; D052240:Fanconi Anemia Complementation Group L Protein; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases