Poly-(ADP-ribose) polymerase-1 (Parp-1) binds in a sequence-specific manner at the Bcl-6 locus and contributes to the regulation of Bcl-6 transcription.
Bcl-6 is a transcription factor that is normally expressed in germinal centre B cells. It is essential for the formation of germinal centres and the production of high-affinity antibodies. Transcriptional downregulation of Bcl-6 occurs on terminal differentiation to plasma cells. Bcl-6 is highly expressed in B-cell non-Hodgkin's lymphoma and, in a subset of cases of diffuse large cell lymphoma, the mechanism of Bcl-6 overexpression involves interruption of normal transcriptional controls. Transcriptional control of Bcl-6 is, therefore, important for normal antibody responses and lymphomagenesis, but little is known of the cis-acting control elements. This report focuses on a region of mouse/human sequence homology in the first intron of Bcl-6, which is a candidate site for such a control element. We demonstrate that poly-(ADP-ribose) polymerase-1 (Parp-1) binds in vitro and in vivo to specific sequences in this region. We further show that PARP inhibitors, and Parp-1 knockdown by siRNA induce Bcl-6 mRNA expression in Bcl-6 expressing cell lines. We speculate that Parp-1 activation plays a role in switching off Bcl-6 transcription and subsequent B-cell exit from the germinal centre.
Ambrose
H E
HE
Division of Investigative Sciences, Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK.
Papadopoulou
V
V
Beswick
R W
RW
Wagner
S D
SD
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005819:Genetic Markers; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D011817:Rabbits; D017385:Sequence Homology
C084103:BCL6 protein, human; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D051560:Proto-Oncogene Proteins c-bcl-6; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases