Poly(ADP-ribosylation) of DNA Topoisomerase I: A Nuclear Response to DNA-strand Interruptions

Enzymes acting at strand interruptions in DNA

“…A model is shown in figure 1. In apparent agreement with this scheme of events, several reports have appeared on the stimulation of homologous recombination, gene amplification and sister chro matid exchange by inhibition of poly(ADP-ribose) synthesis (Oikawa et al 1980;Natarajan et al 1981;Ferro et al 1984;Waldman & Waldman 1991;Smulson et al 1994). More definite experimental tests of the model in cell-free systems (Kawasaki et al 1994) should now be possible however, cell lines or transgenic mice lacking poly (ADP-ribose) polymerase might be required to confirm finally the physiological roles of this enzyme.…”

“…Thus, the overall effect of poly(ADP-ribose) polymerase on repair of DNA strand interruptions, resulting in a slight delay of DNA rejoining, does not appear to be the primary reason for the synthesis of long chains of poly(ADP-ribose), but a secondary consequence. A number of scenarios have been proposed to explain the occurrence of polymer syn thesis, such as wilful depletion of cellular NAD pools (Berger 1985), inhibition of DNA topoisomerase I (Ferro et al 1984), or histone rearrangements in chromatin (Panzeter et al 1993), but none of these models seems particularly convincing. Interestingly, in lower eukaryotes, there seems to be a marked cor relation between the occurrence of poly(ADP-ribose) polymerase and its accompanying poly(ADP-ribose) glycohydrolase with the abundance of repeated DNA sequences in the cellular genome (Satoh et al 1994).…”

A Serendipitous Path to Pharmacology

“…Starting my independent research by running two different laboratories was the major factor that led me to a pharmacologically oriented career. The lab in Kansas continued the work in the field of DNA metabolism and focused on how discontinuous DNA synthesis was carried out as well as on nonoxidation/reduction reactions that involved NAD (8)(9)(10)(11)(12)(13)(14)(15). I had wanted to carry out the same work in the Philippines, but this was not possible.…”