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Permanent cell cycle exit in G 2 phase after DNA damage in normal human fibroblasts
Author(s) -
Baus Fabienne,
Gire Véronique,
Fisher Daniel,
Piette Jacques,
Dulić Vjekoslav
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg387
Subject(s) - biology , restriction point , microbiology and biotechnology , dna damage , mitosis , cell cycle , cdk inhibitor , cyclin dependent kinase 1 , cell cycle checkpoint , cytokinesis , cyclin dependent kinase , cyclin a , mitotic exit , cyclin b1 , cyclin , cell division , cell , dna , genetics , anaphase
Although the Cdk inhibitor p21 Waf1/Cip1 , one of the transcriptional targets of p53, has been implicated in the maintenance of G 2 arrest after DNA damage, its function at this stage of the cell cycle is not really understood. Here, we show that the exposure of normal human fibroblasts (NHFs) to genotoxic agents provokes permanent cell cycle exit in G 2 phase, whereas mouse embryo fibroblasts and transformed human cells progress through mitosis and arrest in G 1 without intervening cytokinesis. p21 Waf1/Cip1 exerts a key role in driving this G 2 exit both by inhibiting cyclin B1–Cdk1 and cyclin A–Cdk1/2 complexes, which control G 2 /M progression, and by blocking the phosphorylation of pRb family proteins. NHFs with compromised pRb proteins could still efficiently arrest in G 2 but were unable to exit the cell cycle, resulting in cell death. Our experiments show that, when under continuous genotoxic stress, normal cells can reverse their commitment to mitotic progression due to passage through the restriction point and that mechanisms involving p21 Waf1/Cip1 and pocket proteins can induce exit in G 2 and G 1 .