DNA-TOPOISOMERASE-I - CUSTOMS OFFICER AT THE BORDER BETWEEN DNA AND RNA WORLDS

DNA topoisomerase I is required for the normal development of multicel lular organisms, probably because it plays a role in controlling gene activity, in addition to its function in relieving tortional stress du ring DNA replication and transcription. The discovery of DNA topoisome rase I as a specific kinase that phosphorylates serine-arginine rich ( SR) splicing factors may provide new insights into their precise funct ion in regulating gene expression. It is clear that the splicing facto rs phosphorylated by DNA topoisomerase I can modulate gene expression by changing the splicing pattern of structural genes. Studies of the s plicing mechanism suggest that the phosphorylation of serine residues of SR proteins contribute to their activity. As this phosphorylation c an be accomplished by several kinases, it remains to be determined whe ther phosphorylation by DNA topoisomerase I protein kinase is the limi ting step in regulating this process. The availability of specific inh ibitors of DNA topoisomerase I, structurally related to the alkaloid c amptothecin, have made it possible to address this question experiment ally. These inhibitors, which hold great promise as antineoplastic dru gs, lead to specific inhibition of SR protein phosphorylation in cultu red cells. This observation will hopefully lend to improved understand ing of the mechanism by which these drugs act at cellular level.