Fanconi anemia group A and C double-mutant mice: functional evidence for a multi-protein Fanconi anemia complex.
OBJECTIVE
Fanconi anemia (FA) is a genetically heterogeneous disorder associated with defects in at least eight genes. The biochemical function(s) of the FA proteins are unknown, but together they define the FA pathway, which is involved in cellular responses to DNA damage and in other cellular processes. It is currently unknown whether all FA proteins are involved in controlling a single function or whether some of the FA proteins have additional roles. The aim of this study was 1) to determine whether the FA group A and group C genes have identical or partially distinct functions, and 2) to have a better model for human FA.


METHODS
We generated mice with a targeted mutation in fanca and crossed them with fancc disrupted animals. Several phenotypes including sensitivity to DNA cross linkers and ionizing radiation, hematopoietic colony growth, and germ cell loss were analyzed in fanca-/-, fancc-/-, fanca/fancc double -/-, and controls.


RESULTS
Fibroblast cells and hematopoietic precursors from fanca/fancc double-mutant mice were not more sensitive to MMC than those of either single mutant. fanca/fancc double mutants had no evidence for an additive phenotype at the cellular or organismal level.


CONCLUSIONS
These results support a model where both FANCA and FANCC are part of a multi-protein nuclear FA complex with identical function in cellular responses to DNA damage and germ cell survival.
Noll
Meenakshi
M
Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, OR 97201, USA. nollm@ohsu.edu
Battaile
Kevin P
KP
Bateman
Raynard
R
Lax
Timothy P
TP
Rathbun
Keany
K
Reifsteck
Carol
C
Bagby
Grover
G
Finegold
Milton
M
Olson
Susan
S
Grompe
Markus
M
D000818:Animals; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D003114:Colony-Forming Units Assay; D003432:Cross-Linking Reagents / Q000633:toxicity; D003433:Crosses, Genetic; D016207:Cytokines / Q000494:pharmacology; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D005720:Gamma Rays; D005816:Genetic Complementation Test; D018740:Genetic Heterogeneity; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011836:Radiation Tolerance / Q000235:genetics; D017384:Sequence Deletion; D013737:Testis / Q000473:pathology
D018797:Cell Cycle Proteins; D003432:Cross-Linking Reagents; D016207:Cytokines; D004268:DNA-Binding Proteins; C120277:Fanca protein, mouse; C497652:Fancc protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D011506:Proteins; D004247:DNA