Damage-resistant DNA synthesis in Fanconi anemia cells treated with a DNA gross-linking agent

Fanconi anemia (FA) is a recessive disorder associated with diverse congeni tal anomalies, progressive bone marrow failure, and a marked predisposition to develop cancer. At the cellular level, FA is characterized by a prolong ed G(2) phase in proliferating cells and a marked hypersensitivity to both the cytotoxic and the clastogenic effects of agents which produce DNA inter strand cross-links. Treatment with these agents leads to even further prolo ngation of the G(2) phase in FA cells. We now show that FA cells, from four different complementation groups, fail to decrease their rates of replicat ive DNA synthesis, as do normal cells, following treatment with a DNA cross -linking agent. This may be responsible for the prolongation of the G2 phas e seen in these cells, and suggests that the fundamental defect in response of FA cells to DNA crosslinking agents may be in the S phase, rather than the G(2) phase, of the cell cycle. (C) 2000 Academic Press.