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Correction of the Fanconi anemia phenotype
Author(s) -
Lambert William Clark,
Centurion Santiago A.,
Patterson Wanda,
Brown Monique Meramo
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a217-a
Subject(s) - fanconi anemia , psoralen , clonogenic assay , clastogen , microbiology and biotechnology , trypan blue , cytotoxic t cell , methoxsalen , cancer research , cell culture , dna synthesis , biology , dna repair , chemistry , genetics , immunology , genotoxicity , dna , medicine , in vitro , toxicity , psoriasis
Fanconi anemia (FA) is a recessively inherited disorder characterized by bone marrow failure, leukemia, numerous cancers and hypersensitivity to DNA interstrand cross‐linking agents (ICLs). We have shown that FA cells fail to reduce their rates of replicative DNA synthesis following treatment with ICLs. We now examined the effect of artificially slowing S‐phase DNA synthesis on clastogenicity and cytotoxicity in FA cells induced by the ICL, 8‐methoxy‐psoralen plus ultraviolet A radiation (PUVA). Cells from normal subjects and from patients with FA, complementation groups A, B, C, and G were subjected to PUVA. Cells were then treated or not with 2.5 mM hydroxyurea (HU) to inhibit DNA synthesis. All FA cells were hypersensitive to the clastogenic and cytotoxic effects of PUVA, as determined by chromosome analysis, trypan blue exclusion and colony forming ability. Addition of HU corrected the hypersensitivity to the clastogenic effects of PUVA by greater than 75 % in all FA cell lines with the greatest correction, 154%, seen in the FA‐G cell line. The clonogenic survival assays showed long term viability corrections greater than 75 % in all cell lines with the greatest correction, 147 %, again seen in FA‐G cells. Thus, failure of S‐phase arrest is an important factor, and may be the most important factor, determining the marked hypersensitivity of FA cells to ICLs. Supported by the Fanconi Anemia Research Fund and NIH.