TRANSCRIPTIONAL REGULATION AND AUTOREGULATION OF THE HUMAN GENE FOR ADP-RIBOSYLTRANSFERASE

Human nuclear poly(ADP-ribosyl)transferase (ADPRT) modifies proteins w ith branched ADP-ribose-polymers. Various proteins, including ADPRT it self, serve as accepters for polyADP-ribose. Target proteins include t hose controlling basic cellular processes such as DNA repair, differen tiation and proliferation. Because of the outstanding features of this enzyme: automodification, several functional domains and central role in physiology of the cell, the molecular biology of ADPRT gained wide interest. The promoter structure contains several CCAAT/TATA boxes an d SP1 sites. However, there is no CCAAT/TATA box in the neighbourhood of an SP1 site and, thus no obvious site for initiation of transcripti on. Within this region there are several noteworthy inverted repeats, which by internal basepairing could form two types of cruciform struct ures. Deletion analysis revealed that these cruciform structures have functional significance. Removal of one type increases the promoter ac tivity, whereas removal of the other diminishes the promoter function. Overexpression of ADPRT from heterologous promoters (MMTV, SV40) lead s to repression of the activity of the ADPRT promoter. Indeed, ADPRT w as shown to bind specifically to one type of cruciform structure. This specific interaction indicates autorepression of the ADPRT gene: the enzyme ADPRT acts directly as a negative modulator of the activity of its own promoter.