The 4N cell cycle delay in Fanconi anemia reflects growth arrest in late S phase.
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.
Akkari
Y M
YM
Department of Molecular and Medical Genetics, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road L103, Portland, Oregon 97201, USA. akkariy@oshu.edu
Bateman
R L
RL
Reifsteck
C A
CA
D'Andrea
A D
AD
Olson
S B
SB
Grompe
M
M
D002460:Cell Line; D019457:Chromosome Breakage; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA; D004260:DNA Repair; D005199:Fanconi Anemia / Q000235:genetics / Q000503:physiopathology*; D005347:Fibroblasts; D054856:G-Quadruplexes; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D014307:Trioxsalen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014466:Ultraviolet Rays
D003432:Cross-Linking Reagents; C016507:hydroxymethyltrioxsalen; D004247:DNA; D014307:Trioxsalen