Akkari Y M, Bateman R L, Reifsteck C A, D'Andrea A D, Olson S B, Grompe M
Department of Molecular and Medical Genetics, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road L103, Portland, Oregon 97201, USA.
Mol Genet Metab. 2001 Dec;74(4):403-12. doi: 10.1006/mgme.2001.3259.
Fanconi anemia (FA) is a human genetic disorder characterized by hypersensitivity to DNA crosslinking agents. Its cellular phenotypes include increased chromosome breakage and a marked cell-cycle delay with 4N DNA content after introduction of interstrand DNA crosslinks (ICL). To further understand the nature of this delay previously described as a G2/M arrest, we introduced ICL specifically during G2 and monitored the cells for passage into mitosis. Our results showed that, even at the highest doses, postreplication ICL produced neither G2/M arrest nor chromosome breakage in FA-A or FA-C cells. This suggests that, similar to wild-type cells, DNA replication is required to trigger both responses. Therefore, the 4N cell DNA content observed in FA cells after ICL treatment also represents incomplete DNA replication and arrest in late S phase. FA fibroblasts from complementation groups A and C were able to recover from the ICL-induced cell-cycle arrest, but took approximately 3 times longer than controls. These results indicate that the FA pathway is required for the efficient resolution of ICL-induced S-phase arrest.
范可尼贫血（FA）是一种人类遗传性疾病，其特征是对DNA交联剂高度敏感。其细胞表型包括染色体断裂增加以及在引入链间DNA交联（ICL）后出现明显的细胞周期延迟，且DNA含量为4N。为了进一步了解先前被描述为G2/M期阻滞的这种延迟的本质，我们在G2期特异性地引入ICL，并监测细胞进入有丝分裂的情况。我们的结果表明，即使在最高剂量下，复制后ICL在FA - A或FA - C细胞中既不会导致G2/M期阻滞，也不会引起染色体断裂。这表明，与野生型细胞类似，DNA复制是触发这两种反应所必需的。因此，ICL处理后在FA细胞中观察到的4N细胞DNA含量也代表DNA复制不完全以及在S期后期停滞。来自互补组A和C的FA成纤维细胞能够从ICL诱导的细胞周期停滞中恢复，但所需时间比对照长约3倍。这些结果表明，FA途径对于有效解决ICL诱导的S期停滞是必需的。
