Arrest of S-phase progression is impaired in Fanconi anemia cells

Fanconi anemia (FA) is an inherited cancer-susceptibility disorder, charact erized by genomic instability, hypersensitivity to DNA cross-linking agents , and a prolonged G2 phase of the cell cycle. We observed a marked dose-dep endent accumulation of FA cells in the G2 compartment after treatment with 4,5',8-trimethylpsoralen (Me(3)Pso) in combination with 365 nm irradiation. Using bivariate DNA distribution methodology, we determined the proportion of replicating and arresting S-phase cells and observed that, whereas norm al cells arrested DNA replication in the presence of Me(3)Pso cross-links a nd monoadducts, FA lymphoblasts failed to arrest DNA synthesis. Taken toget her, the above data suggest that, in response to damage induced by DNA cros s-linking agents, the S-phase checkpoint is inefficient in FA cells. This w ould lead to accumulation of secondary lesions, such as single- and double- strand breaks and gaps. The prolonged time in G2 phase seen in FA cells the refore exists in order to allow the cells to remove lesions which accumulat ed during the preceding abnormal S phase, (C) 2000 Academic Press.