ROLE OF P21(WAF1 CIP1/SD1) IN CELL-DEATH AND DNA-REPAIR AS STUDIED USING A TETRACYCLINE-INDUCIBLE SYSTEM IN P53-DEFICIENT CELLS/

Postulated roles for p21(Waf1/Cip1/Sdi1) (p21) in DNA repair and apopt osis remain controversial. Studies suggest both stimulatory and inhibi tory effects of p21 in DNA repair. p21 has also been implicated in ind uction or protection from apoptosis. Using the tetracycline inducible expression system, we studied the role of p21 in DNA repair and apopto sis in wild-type p53 deficient DLD1 colorectal carcinoma cells. These cells displayed marked heterogeneity in their ability to tolerate high er levels of exogenous p21, The majority of the p21 overexpressing cel ls grew slower and did not exhibit apoptotic phenotype, some cells und erwent apoptotic death within 5-8 days following p21 induction while o ther became giant cells prior to undergoing cell death. Induction of p 21 transgene neither sensitized to nor protected from adriamycin-induc ed acute cell death. p21 also did not alter the clonogenic survival fo llowing adriamycin treatment. Clonogenic survival u.v.-irradiation was , however, increased when p21 expression was transiently induced a few hours before and after u.v.-irradiation. Consistent with its effect o n clonogenic survival, p21 also enhanced the cellular capacity to repa ir three different exogenously introduced u.v.-damaged reporter plasmi ds. Taken together our results demonstrate that p21 may modulate the n ucleotide excision repair process to facilitate the repair of u.v.-typ e DNA damage even in the absence of wild-type p53.