p21(cip-1/waf-1) deficiency causes deformed nuclear architecture, centriole overduplication, polyploidy, and relaxed microtubule damage checkpoints in human hematopoietic cells

A recent hypothesis suggests that tumor-specific killing by radiation and c hemotherapy agents is due to defects or loss of cell cycle checkpoints. An important component of some checkpoints is p53-dependent induction of p21(c ip-1/waf-1). Both p53 and p21 have been shown to be required for microtubul e damage checkpoints in mitosis and in G1 phase of the cell cycle and they thus help to maintain genetic stability. We present here evidence that p21( cip-1/waf-1) deficiency relaxes the G1 phase microtubule checkpoint that is activated by microtubule damage induced with nocodazole, Reduced p21(cip-1 /waf-1) expression also results in gross nuclear abnormalities and centriol e overduplication, p53 has already been implicated in centrosome regulation . Our findings further suggest that the p53/p21 axis is involved in a check point pathway that links the centriole/centrosome cycle and microtubule org anization to the DNA replication cycle and thus helps to maintain genomic i ntegrity. The inability to efficiently upregulate p21(cip-1/waf-1) in p21(c ip-1/waf-1) antisense-expressing cells in response to microtubule damage co uld uncouple the centrosome cycle from the DNA cycle and lead to nuclear ab normalicies and polyploidy, A centrosome duplication checkpoint could be a new target for novel chemotherapy strategies. (C) 1999 by The American Soci ety of Hematology.