Defects in transcription coupled repair interfere with expression of p90(MDM2) in response to ultraviolet light

Ultraviolet (UV) irradiation transiently stabilizes p53 through a mechanism that may require a decrease in the activity of the ubiquitin ligase, p90(M DM2). Conversely, the recovery of low levels of p53 following UV exposure m ay depend on an increase in p90(MDM2). The level of p90(MDM2) is increased by UV light following the p53-dependent induction of an internal mdm2 promo ter, P2. If this induction of mdm2 were critical for the recovery of low le vels of p53 following UV exposure, defects in mdm2's transcription would re sult in a prolonged increase in p53. Cells defective in transcription coupl ed repair (TCR) maintain high levels of p53 for a prolonged period followin g UV exposure. Such cells also have defects in general transcription after UV irradiation. We investigated whether TCR-deficient cells express diminis hed levels of mdm2 mRNA and p90(MDM2) following UV exposure. We found that transcription of mdm2 was reduced in TCR-deficient cells. The uninducible m dm2 promoter, P1, was more sensitive to the inhibitory effects of UV irradi ation than the P2 promoter. The decrease in transcription from the P1 promo ter was sufficient to reduce the level of p90(MDM2) and correlated with a p rolonged increase in p53. Thus, p53-independent transcription of mdm2 appea rs critical to p53's regulation.