Dual regulation of AP-2alpha transcriptional activation by poly(ADP-ribose) polymerase-1.
Poly(ADP-ribose) polymerase-1 (PARP-1) is a co-activator for AP-2alpha (activator protein 2alpha)-mediated transcriptional activation. In the present study, we find that the role of PARP-1 in AP-2alpha transcription is distinctly dualistic with opposing effects. Separate regions of PARP-1 interact with AP-2alpha and independently control its transcriptional activation. The C-terminus containing the catalytic domain strongly interacts with AP-2alpha, whereas low-affinity binding is seen in the middle region, which includes the breast-cancer susceptibility gene 1 C-terminal domain and automodification region. The middle region enhances AP-2alpha transcription. Even portions of this region independently interact and have partial effects on transcription. The catalytic domain strongly poly-(ADP-ribosyl)ates AP-2alpha. This modification, on the other hand, affects its DNA binding. 3-Aminobenzamide and 6(5H)-phenanthridinone that inhibit the enzymic activity significantly enhance the binding of AP-2alpha to its target sequence and increase its transcriptional activity. The enzymic activity of PARP-1 is known to be induced by stress conditions that damage cellular DNA, and the poly(ADP-ribosyl)ation of target proteins is transient in nature with a half-life of less than a minute. We hypothesize that PARP-1 enhances the transcriptional activity of AP-2alpha in normal circumstances, whereas its enzymic activity is used as a temporary shut-off mechanism during unfavourable conditions.
Li
Min
M
MetroHealth Medical Center, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA.
Naidu
Padmavathy
P
Yu
Yihong
Y
Berger
Nathan A
NA
Kannan
Perry
P
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D025941:Protein Interaction Mapping / Q000379:methods; D011499:Protein Processing, Post-Translational / Q000502:physiology; D018243:Teratocarcinoma / Q000473:pathology; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
D004268:DNA-Binding Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C493673:TFAP2A protein, human; C493668:Tfap2a protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases