Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

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

Oncogene volume 26, pages 6244–6252 (2007)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Akiyama T, Takasawa S, Nata K, Kobayashi S, Abe M, Shervani NJ et al. (2001). Activation of Reg gene for insulin producing beta cell regeneration: poly(ADP)-ribose polymerase binds Reg promoter and regulates the transcription by autopoly(ADP)-ribosylation. Proc Natl Acad Sci USA 98: 48–53.

    CAS  PubMed  Google Scholar 

  • Ame JC, Spenlehauer C, de Murcia G . (2004). The PARP superfamily. Bioessays 26: 882–893.

    Article  CAS  Google Scholar 

  • Amiri KI, Ha HC, Smulson ME, Richmond A . (2006). Differential regulation of CXC ligand 1 transcription in melanoma cell lines by poly(ADP-ribose) polymerase-1. Oncogene 25: 7714–7722.

    Article  CAS  Google Scholar 

  • Bereschenko OR, Gu W, Dalla-Favera R . (2002). Acetylation inactivates the transcriptional repressor Bcl-6. Nat Genet 32: 606–613.

    Article  Google Scholar 

  • Bernardin F, Collyn-d’Hooghe M, Quief S, Bastard C, Leprince D, Kerckaert J . (1997). Small deletions occur in highly conserved regions of the LAZ3/BCL6 major translocation cluster in one case of non-Hodgkin's lymphoma without 3q27 translocation. Oncogene 14: 849–855.

    Article  CAS  Google Scholar 

  • Borggrefe T, Wabl M, Akhmedov AT, Jessberger R . (1998). A B-cell specific recombination complex. J Biol Chem 273: 17025–17035.

    Article  CAS  Google Scholar 

  • Bross L, Fukita Y, McBlane F, Demolliere C, Rajewsky K, Jacobs H . (2000). DNA double-strand breaks in immunoglobulin genes undergoing somatic hypermutation. Immunity 13: 589–597.

    Article  CAS  Google Scholar 

  • Butler AJ, Ordahl CP . (1999). Poly(ADP-ribose) polymerase binds with transcription enhancer factor 1 to MCAT1 elements to regulate muscle specific transcription. Mol Cell Biol 19: 296–306.

    Article  CAS  Google Scholar 

  • Cattoretti G, Chang C, Cechova K, Zhang B, Ye B, Falini B et al. (1995). BCL-6 protein is expressed in germinal-center B cells. Blood 86: 45–53.

    CAS  Google Scholar 

  • Cervellera MN, Sala A . (2000). Poly(ADP-ribose) polymerase is a B-myb coactivator. J Biol Chem 275: 10692–10696.

    Article  CAS  Google Scholar 

  • Chang C, Ye B, Chaganti R, Dalla-Favera R . (1996). BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. Proc Natl Acad Sci USA 93: 6947–6952.

    Article  CAS  Google Scholar 

  • Chapman MA, Donaldson IJ, Gilbert J, Grafham D, Rogers J, Green A et al. (2004). Analysis of multiple genomic sequence alignments: a web resource, online tools, and lessons learned from analysis of mammalian SCL loci. Genome Res 14: 313–318.

    Article  CAS  Google Scholar 

  • Chattopadhyay A, Tate SA, Beswick RW, Wagner SD, Ko Ferrigno P . (2006). A peptide aptamer to antagonize BCL-6 function. Oncogene 25: 2223–2233.

    Article  CAS  Google Scholar 

  • Chevallier N, Corcoran CM, Lennon C, Hyjek E, Chadburn A, Bardwell VJ et al. (2004). ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cell lymphoma oncoprotein. Blood 103: 1454–1463.

    Article  CAS  Google Scholar 

  • D’Amours D, Desnoyers S, D’Silva I, Poirier GG . (1999). Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 342 (Part 2): 249–268.

    Article  Google Scholar 

  • Dent A, Shaffer A, Yu X, Allman D, Staudt L . (1997). Control of inflammation, cytokine expression and germinal centre formation by BCL-6. Science 276: 589–592.

    Article  CAS  Google Scholar 

  • Durkacz BW, Omidiji O, Gray DA, Shall S . (1980). ADP-ribose)n participates in DNA excision repair. Nature 283: 593–596.

    Article  CAS  Google Scholar 

  • Fujita N, Jaye DL, Geigerman C, Akyildiz A, Mooney MR, Boss JM et al. (2004). MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Cell 119: 75–86.

    Article  CAS  Google Scholar 

  • Gottgens B, Gilbert J, Barton L, Grafham D, Rogers J, Bentley D et al. (2001). Long-range comparison of human and mouse SCL loci: localized regions of sensitivity to restriction endonucleases correspond precisely with peaks of conserved noncoding sequences. Genome Res 11: 87–97.

    Article  CAS  Google Scholar 

  • Gregory CD, Rowe M, Rickinson AB . (1990). Different Epstein-Barr virus-B-cell interactions in phenotypically distinct clones of a Burkitt's lymphoma cell line. J Gen Virol 71 (Part 7): 1481–1495.

    Article  CAS  Google Scholar 

  • Haince JF, Rouleau M, Poirier GG . (2006). Transcription. Gene expression needs a break to unwind before carrying on. Science 312: 1752–1753.

    Article  CAS  Google Scholar 

  • Hassa PO, Covic M, Hasan S, Imhof R, Hottiger MO . (2001). The enzymatic and DNA binding activity of PARP-1 are not required for NF-κB coactivator function. J Biol Chem 276: 45588–45597.

    Article  CAS  Google Scholar 

  • Huang K, Tidyman WE, Le K-UT, Kirsten E, Kun E, Ordahl CP . (2004). Analysis of nucleotide sequence dependent binding of poly(ADP-ribose) polymerase in a purified system. Biochemistry 43: 217–223.

    Article  CAS  Google Scholar 

  • Huber A, Bai P, de Murcia J, de Murcia G . (2004). PARP-1, PARP-2 and ATM in the DNA damage response: functional synergy in mouse development. DNA Repair (Amst) 3: 1103–1108.

    Article  CAS  Google Scholar 

  • Huynh KD, Bardwell VJ . (1998). The BCL-6 POZ domain and other POZ domains interact with the co-repressors N-CoR and SMRT. Oncogene 17: 2473–2484.

    Article  CAS  Google Scholar 

  • Ju BG, Lunyak VV, Perissi V, Garcia-Bassets I, Rose DW, Glass CK et al. (2006). A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science 312: 1798–1802.

    Article  CAS  Google Scholar 

  • Ju BG, Solum D, Song EJ, Lee KJ, Rose DW, Glass CK et al. (2004). Activating the PARP-1 sensor component of the groucho/ TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway. Cell 119: 815–829.

    Article  CAS  Google Scholar 

  • Kikuchi M, Miki T, Kumagai T, Fukuda T, Kamiyama R, Miyasaka N et al. (2000). Identification of negative regulatory regions within the first exon and intron of the BCL-6 gene. Oncogene 19: 4941–4945.

    Article  CAS  Google Scholar 

  • Kim MY, Mauro S, Gevry N, Lis JT, Kraus WL . (2004). NAD+-dependent modulation of chromatin structure and transcription by nucleosome binding properties of PARP-1. Cell 119: 803–814.

    Article  CAS  Google Scholar 

  • Kraus WL, Lis JT . (2003). PARP goes transcription. Cell 113: 677–683.

    Article  CAS  Google Scholar 

  • Lonskaya I, Potaman VN, Shlyakhtenko LS, Oussatcheva EA, Lyubchenko YL, Soldatenkov VA . (2005). Regulation of poly(ADP-ribose) polymerase-1 by DNA structure-specific binding. J Biol Chem 280: 17076–17083.

    Article  CAS  Google Scholar 

  • Ma L, Wortis HH, Kenter AL . (2002). Two new isotype specific switching activities detected for immunoglobulin class switching. J Immunol 168: 2835–2846.

    Article  CAS  Google Scholar 

  • Margalit O, Amram H, Amariglio N, Simon AJ, Shaklai S, Granot Ge et al. (2006). BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma. Blood 107: 1599–1607.

    Article  CAS  Google Scholar 

  • Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G . (1998). XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol 18: 3563–3571.

    Article  CAS  Google Scholar 

  • Nirodi C, NagDas S, Gygi SP, Olson G, Aebersold R, Richmond A . (2001). A role for poly(ADP-ribose) polymerase in the transcriptional regulation of the melanoma growth stimulatory activity (CXCL1) gene expression. J Biol Chem 276: 9366–9374.

    Article  CAS  Google Scholar 

  • Niu H, Ye B, Dalla-Favera R . (1998). Antigen receptor signaling induces MAP kinase mediated phosphorylation and degradation of the Bcl-6 transcription factor. Genes Dev 12: 1953–1961.

    Article  CAS  Google Scholar 

  • Offit K, Lo Coco F, Louie DC, Parsa NZ, Leung D, Portlock C et al. (1994). Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma. N Engl J Med 331: 74–80.

    Article  CAS  Google Scholar 

  • Ouararhni K, Hadj-Slimane R, Ait-Si-Ali S, Robin P, Mietton F, Harel-Bellan A et al. (2006). The histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity. Genes Dev 20: 3324–3336.

    Article  CAS  Google Scholar 

  • Pasqualucci L, Migliazza A, Basso K, Houldsworth J, Chaganti R, Dalla-Favera R . (2003). Mutations of the BCL-6 proto-oncogene disrupt its negative autoregulation in diffuse large cell lymphoma. Blood 101: 2914–2923.

    Article  CAS  Google Scholar 

  • Pavri R, Lewis B, Kim TK, Dilworth FJ, Erdjument-Bromage H, Tempest P et al. (2005). PARP-1 determines specificity in a retinoid signaling pathway via direct modulation of mediator. Mol Cell 18: 83–96.

    Article  CAS  Google Scholar 

  • Pirrotta V . (2003). Transcription: puffing with PARP. Science 299: 528–529.

    Article  CAS  Google Scholar 

  • Poirier GG, de Murcia G, Jongstra-Bilen J, Niedergang C, Mandel P . (1982). Poly(ADP)-ribosylation of polynucleosomes causes relaxation of chromatin structure. Proc Natl Acad Sci USA 79: 3423–3427.

    Article  CAS  Google Scholar 

  • Polo JM, Dell’Oso T, Ranuncolo SM, Cerchietti L, Beck D, Da Silva GF et al. (2004). Specific peptide interference reveals Bcl-6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Nat Medicine 10: 1329–1335.

    Article  CAS  Google Scholar 

  • Potaman VN, Shlyakhtenko LS, Oussatcheva EA, Lyubchenko YL, Soldatenkov VA . (2005). Specific binding of poly(ADP-ribose)polymerase to cruciform hairpins. J Mol Biol 348: 609–615.

    Article  CAS  Google Scholar 

  • Rouleau M, Aubin RA, Poirier GG . (2004). Poly(ADP)-ribosylated chromatin domains: access granted. J Cell Science 117 (Part 6): 815–825.

    Article  CAS  Google Scholar 

  • Sale JE, Neuberger MS . (1998). TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B-cell line. Immunity 9: 859–869.

    Article  CAS  Google Scholar 

  • Satoh MS, Lindahl T . (1992). Role of poly(ADP-ribose) formation in DNA repair. Nature 356: 356–358.

    Article  CAS  Google Scholar 

  • Schreiber E, Matthias P, Müller M, Schaffner W . (1989). Rapid detection of octamer binding protein with ‘mini-extracts’ prepared from a small number of cells. Nucl Acids Res 17: 6419.

    Article  CAS  Google Scholar 

  • Schreiber V, Dantzer F, Ame JC, de Murcia G . (2006). Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7: 517–528.

    Article  CAS  Google Scholar 

  • Simbulan-Rosenthal CM, Rosenthal DS, Luo R, Samara R, Espinoza LA, Hassa PO et al. (2003). PARP-1 binds E2F-1 independently of its DNA binding and catalytic domains, and acts as a novel coactivator of E2F-1-mediated transcription during re-entry of quiescent cells into S phase. Oncogene 22: 8460–8471.

    Article  CAS  Google Scholar 

  • Soldatenkov VA, Chasovskikh S, Potaman VN, Trofimova I, Smulson ME, Dritshilo A . (2002). Transcriptional repression by binding of poly(ADP-ribose)polymerase to promoter sequences. J Biol Chem 277: 665–670.

    Article  CAS  Google Scholar 

  • Walker SR, Nelson EA, Frank DA . (2007). STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas. Oncogene 26: 224–233.

    Article  CAS  Google Scholar 

  • Wang X, Li Z, Naganuma A, Ye B . (2002). Negative autoregulation of BCL-6 is bypassed by genetic alterations in diffuse large B cell lymphomas. Proc Natl Acad Sci USA 99: 15018–15023.

    Article  CAS  Google Scholar 

  • Ye B, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R et al. (1997). The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 16: 161–170.

    Article  CAS  Google Scholar 

  • Ye B, Chaganti S, Chang C, Niu H, Corradini P, Chaganti R et al. (1995). Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. EMBO J 14: 6209–6217.

    Article  CAS  Google Scholar 

  • Ye B, Lista F, Lo Coco F, Knowles D, Offit K, Chaganti R et al. (1993). Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 262: 747–750.

    Article  CAS  Google Scholar 

  • Zhang Z, Hildebrandt EF, Simbulan-Rosenthal CM, Anderson MG . (2002). Sequence specific binding of poly-(ADP-ribose) polymerase-1 to the human T cell leukaemia virus type-1 tax responsive element. Virology 296: 107–116.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Wellcome Trust and Lymphoma Research Trust to SDW. SynPlot analysis was carried out by Dr Ian Donaldson, Department of Haematology, Cambridge. MUTU I and MUTU III were gifts from Professor Alan Rickinson, Birmingham.

Author information

Authors and Affiliations

  1. Division of Investigative Sciences, Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK

    H E Ambrose, V Papadopoulou, R W Beswick & S D Wagner

Authors
  1. H E Ambrose
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V Papadopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R W Beswick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S D Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S D Wagner.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ambrose, H., Papadopoulou, V., Beswick, R. et al. 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. Oncogene 26, 6244–6252 (2007). https://doi.org/10.1038/sj.onc.1210434

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210434

Keywords

This article is cited by

Search

Advanced search

Quick links