Inhibition of DNA ligase activity by histones and its reversal by poly(ADP-ribose).
The molecular mechanism by which poly(ADP-ribose) participates in DNA repair was investigated using purified DNA ligase in DNA-histone systems. The ligase activity was markedly inhibited by histones; the inhibition was greater than 80% with histone H1 at concentrations equal to DNA. This inhibition was reversed efficiently by poly(ADP-ribose), either added exogenously or synthesized in situ with poly(ADP-ribose) synthetase. The reversal effect was specific for poly(ADP-ribose); other polyanions such as mRNA, rRNA's, tRNA, and synthetic poly(A) were less effective or totally ineffective. The poly(ADP-ribose) effect appeared to be caused by binding to histones and decreasing DNA-histone interactions. Poly(ADP-ribose) also had high affinity for DNA ligase. These observations, together with the findings of absolute dependence of poly(ADP-ribose) synthetase activity on DNA strand ends and extensive automodification of the synthetase in DNA-damaged cells, suggested a possible mechanism of poly(ADP-ribose) action in DNA repair, in which auto-modified poly(ADP-ribose) synthetase serves as a link between DNA damage and activation of DNA ligase.
D011088:DNA Ligases / Q000037:antagonists & inhibitors*; D004260:DNA Repair; D006657:Histones / Q000494:pharmacology*; D009702:Nucleoside Diphosphate Sugars / Q000494:pharmacology*; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis / Q000494:pharmacology*; D011118:Polynucleotide Ligases / Q000037:antagonists & inhibitors*; D011485:Protein Binding
D006657:Histones; D009702:Nucleoside Diphosphate Sugars; D011064:Poly Adenosine Diphosphate Ribose; D011088:DNA Ligases; D011118:Polynucleotide Ligases