The Fanconi anemia complementation group C gene product

Structural evidence of multifunctionality

Qishen Pang, Tracy A. Christianson, Winifred Keeble, Jane Diaz, Gregory R. Faulkner, Carol Reifsteck, Susan Olson, Graver C. Bagby

Research output: Contribution to journalArticle

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Abstract

The Fanconi anemia (FA) group C gene product (FANCC) functions to protect cells from cytotoxic and genotoxic effects of cross-linking agents. FANCC is also required for optimal activation of STAT1 in response to cytokine and growth factors and for suppressing cytokine-induced apoptosis by modulating the activity of double-stranded RNA-dependent protein kinase. Because not all FANCC mutations affect STAT1 activation, the hypothesis was considered that cross-linker resistance function of FANCC depends on structural elements that differ from those required for the cytokine signaling functions of FANCC. Structure-function studies were designed to test this notion. Six separate alanine-substituted mutations were generated in 3 highly conserved motifs of FANCC. All mutants complemented mitomycin C (MMC) hypersensitive phenotype of FA-C cells and corrected aberrant posttranslational activation of FANCD2 in FA-C mutant cells. However, 2 of the mutants, S249A and E251A, failed to correct defective STAT1 activation. FA-C lymphoblasts carrying these 2 mutants demonstrated a defect in recruitment of STAT1 to the interferon γ (IFN-γ) receptor and GST-fusion proteins bearing S249A and E251A mutations were less efficient binding partners for STAT1 in stimulated lymphoblasts. These same mutations failed to complement the characteristic hypersensitive apoptotic responses of FA-C cells to tumor necrosis factor-α (TNF-α) and IFN-γ. Cells bearing a naturally occurring FANCC mutation (322delG) that preserves this conserved region showed normal STAT1 activation but remained hypersensitive to MMC. The conclusion is that a central highly conserved domain of FANCC is required for functional interaction with STAT1 and that structural elements required for STAT1-related functions differ from those required for genotoxic responses to cross-linking agents. Preservation of signaling capacity of cells bearing the del322G mutation may account for the reduced severity and later onset of bone marrow failure associated with this mutation.

Original languageEnglish (US)
Pages (from-to)1392-1401
Number of pages10
JournalBlood
Volume98
Issue number5
DOIs
StatePublished - Sep 1 2001

Fingerprint

Fanconi Anemia
Bearings (structural)
Genes
Chemical activation
Mutation
Mitomycin
Cytokines
Interferon Receptors
eIF-2 Kinase
Double-Stranded RNA
Alanine
Interferons
Intercellular Signaling Peptides and Proteins
Bone
Fusion reactions
Tumor Necrosis Factor-alpha
Apoptosis
Defects
Bone Marrow
Phenotype

ASJC Scopus subject areas

  • Hematology

Cite this

Pang, Q., Christianson, T. A., Keeble, W., Diaz, J., Faulkner, G. R., Reifsteck, C., ... Bagby, G. C. (2001). The Fanconi anemia complementation group C gene product: Structural evidence of multifunctionality. Blood, 98(5), 1392-1401. https://doi.org/10.1182/blood.V98.5.1392

The Fanconi anemia complementation group C gene product : Structural evidence of multifunctionality. / Pang, Qishen; Christianson, Tracy A.; Keeble, Winifred; Diaz, Jane; Faulkner, Gregory R.; Reifsteck, Carol; Olson, Susan; Bagby, Graver C.

In: Blood, Vol. 98, No. 5, 01.09.2001, p. 1392-1401.

Research output: Contribution to journalArticle

Pang, Q, Christianson, TA, Keeble, W, Diaz, J, Faulkner, GR, Reifsteck, C, Olson, S & Bagby, GC 2001, 'The Fanconi anemia complementation group C gene product: Structural evidence of multifunctionality', Blood, vol. 98, no. 5, pp. 1392-1401. https://doi.org/10.1182/blood.V98.5.1392
Pang Q, Christianson TA, Keeble W, Diaz J, Faulkner GR, Reifsteck C et al. The Fanconi anemia complementation group C gene product: Structural evidence of multifunctionality. Blood. 2001 Sep 1;98(5):1392-1401. https://doi.org/10.1182/blood.V98.5.1392
Pang, Qishen ; Christianson, Tracy A. ; Keeble, Winifred ; Diaz, Jane ; Faulkner, Gregory R. ; Reifsteck, Carol ; Olson, Susan ; Bagby, Graver C. / The Fanconi anemia complementation group C gene product : Structural evidence of multifunctionality. In: Blood. 2001 ; Vol. 98, No. 5. pp. 1392-1401.
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