title: Human FANCC is hypomorphic in murine Fancc-deficient cells.
abstract: Fancc suppresses cross-linker-induced genotoxicity, modulates growth-inhibitory cytokine responses, and modulates endotoxin responses. Although loss of the latter function is known to account for endotoxin-induced marrow failure in murine Fancc (mFancc)-deficient mice, some argue that cytokine and endotoxin hypersensitivities devolve simply from genomic instability. Seeking to resolve this question, we planned to ectopically express instructive human FANCC (hFANCC) mutants in murine Fancc-deficient hematopoietic stem cells. To first assure that hFANCC cDNA was competent in murine cells, we compared hFANCC and mFancc in complementation assays for cross-linking agent hypersensitivity and endotoxin hypersensitivity. We found that mFancc complemented murine Fancc-deficient cells in both assays, but that hFANCC fully suppressed only endotoxin hypersensitivity, not cross-linking agent hypersensitivity. These results support the notions that Fancc is multifunctional and that structural prerequisites for its genoprotective functions differ from those required to constrain endotoxin responses known to lead to marrow failure in Fancc-deficient mice.
authors.affiliation: Portland Veterans Administration Medical Center, Portland, OR 97239, USA. haysl@ohsu.edu
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hays
authors.forename: Winifred W
authors.initials: WW
authors.lastname: Keeble
authors.forename: Jane E
authors.initials: JE
authors.lastname: Yates
authors.forename: R K
authors.initials: RK
authors.lastname: Rathbun
authors.forename: Tara
authors.initials: T
authors.lastname: Koretsky
authors.forename: Susan B
authors.initials: SB
authors.lastname: Olson
authors.forename: Zejin
authors.initials: Z
authors.lastname: Sun
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
mesh_terms: D000818:Animals; D004731:Endotoxins / Q000494:pharmacology; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000139:chemically induced; D051379:Mice; D018345:Mice, Knockout; D019076:Transgenes
chemical_list: D004731:Endotoxins; D052218:Fanconi Anemia Complementation Group C Protein