TY - JOUR
T1 - The 4N cell cycle delay in Fanconi anemia reflects growth arrest in late S phase
AU - Akkari, Yassmine M.N.
AU - Bateman, Raynard L.
AU - Reifsteck, Carol A.
AU - D'Andrea, Alan D.
AU - Olson, Susan B.
AU - Grompe, Markus
N1 - Funding Information:
We thank Petra Jacobs, Jeff Lipps, and Jennifer Wasik for technical assistance. This work was supported by NHLBI Program Project Grant 1PO1HL48546 to M.G.
PY - 2001
Y1 - 2001
N2 - 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 wildtype 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 ∼3 times longer than controls. These results indicate that the FA pathway is required for the efficient resolution of ICL-induced S-phase arrest.
AB - 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 wildtype 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 ∼3 times longer than controls. These results indicate that the FA pathway is required for the efficient resolution of ICL-induced S-phase arrest.
KW - Fanconi anemia
KW - Fanconi anemia group A
KW - Fanconi anemia group C
KW - Interstrand DNA crosslink
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U2 - 10.1006/mgme.2001.3259
DO - 10.1006/mgme.2001.3259
M3 - Article
C2 - 11749045
AN - SCOPUS:0035691754
SN - 1096-7192
VL - 74
SP - 403
EP - 412
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 4
ER -