Fancd2 functions in a double strand break repair pathway that is distinct from non-homologous end joining.
Fanconi anemia (FA) is a multigenic recessive disease resulting in bone marrow failure and increased cancer susceptibility. Cells from FA patients and mouse models are sensitive to DNA interstrand crosslinks (ICLs) and FA mice are moderately sensitive to ionizing radiation (IR). Both kinds of damage induce DNA double strand breaks (DSBs). To date, nine genes in 11 complementation groups have been identified; however, the precise function of the FA pathway remains unclear. Many of the proteins form a nuclear complex necessary for the mono-ubiquitination of the downstream protein, Fancd2. To further investigate the role of the FA pathway in repair of DSBs, we generated Fancd2(-/-)/Prkdc(sc/sc) double mutant mice. Prkdc(sc/sc) mutant mice have a defect in non-homologous end joining (NHEJ) and are sensitive to IR-induced DNA damage. Double mutant animals and primary cells were more sensitive to IR than either single mutant, suggesting that Fancd2 operates in DSB repair pathway distinct from NHEJ. Fancd2(-/-)/Prkdc(sc/sc) double mutant cells were also more sensitive to DSBs generated by a restriction endonuclease. The role of Fancd2 in DSB repair may account for the moderate sensitivity of FA cells to irradiation and FA cells sensitivity to ICLs that are repaired via a DSB intermediate.
Houghtaling
Scott
S
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, 97239, USA. houghtal@ohsu.edu
Newell
Amy
A
Akkari
Yassmine
Y
Taniguchi
Toshiyasu
T
Olson
Susan
S
Grompe
Markus
M
D000818:Animals; D004249:DNA Damage / Q000235:genetics* / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics*; D004262:DNA Restriction Enzymes / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D005838:Genotype; D007259:Infrared Rays; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics / Q000502:physiology; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D004262:DNA Restriction Enzymes