B-aggressive Lymphoma Family Proteins Have Unique Domains That Modulate Transcription and Exhibit Poly(ADP-ribose) Polymerase Activity

Abstract

BAL1 (B-aggressive lymphoma 1) was originally identified as a risk-related gene in diffuse large B-cell lymphoma. BAL1 encodes a nuclear protein with N-terminal macro domains and a putative C-terminal poly(ADP-ribose) polymerase (PARP) active site. Macro domains are sequences homologous to the non-histone region of histone macroH2A. Several lines of evidence suggest that these domains may modulate transcription, including a high concentration of histone macroH2A in the inactive X chromosome, direct interference with transcription factor binding in a positioned nucleosome, and structural similarity to DNA binding domains. Poly(ADP-ribosyl)ation is a critical post-translational modification that regulates chromatin configuration and transcription. In this report we describe two additional BAL family members, BAL2 and BAL3, with N-terminal macro domains and putative C-terminal PARP active sites and assess the function of these specific regions in BAL family members. Herein, we demonstrate that BAL macro domains repress transcription when tethered to a promoter. In addition, we show that BAL2 and BAL3, but not BAL1, exhibit PARP activity. In agreement with these data, BAL1 lacks several critical donor and acceptor residues that are conserved in the BAL2 and -3 PARP active sites. Of interest, BAL family members with inactive or functional PARP domains differed in their ability to repress transcription. BAL family members are the only described proteins with both PARP and macro domains, underscoring the potential functional significance of this unique combination. BAL1 (B-aggressive lymphoma 1) was originally identified as a risk-related gene in diffuse large B-cell lymphoma. BAL1 encodes a nuclear protein with N-terminal macro domains and a putative C-terminal poly(ADP-ribose) polymerase (PARP) active site. Macro domains are sequences homologous to the non-histone region of histone macroH2A. Several lines of evidence suggest that these domains may modulate transcription, including a high concentration of histone macroH2A in the inactive X chromosome, direct interference with transcription factor binding in a positioned nucleosome, and structural similarity to DNA binding domains. Poly(ADP-ribosyl)ation is a critical post-translational modification that regulates chromatin configuration and transcription. In this report we describe two additional BAL family members, BAL2 and BAL3, with N-terminal macro domains and putative C-terminal PARP active sites and assess the function of these specific regions in BAL family members. Herein, we demonstrate that BAL macro domains repress transcription when tethered to a promoter. In addition, we show that BAL2 and BAL3, but not BAL1, exhibit PARP activity. In agreement with these data, BAL1 lacks several critical donor and acceptor residues that are conserved in the BAL2 and -3 PARP active sites. Of interest, BAL family members with inactive or functional PARP domains differed in their ability to repress transcription. BAL family members are the only described proteins with both PARP and macro domains, underscoring the potential functional significance of this unique combination. The BAL1 (B-Aggressive lymphoma 1) gene was originally identified in a genome-wide search for risk-related genes in diffuse large B-cell lymphoma (DLBCL) 3The abbreviations used are: DLBCL, diffuse large B-cell lymphoma; contig, group of overlapping clones; aa, amino acid(s); PARP, poly(ADP-ribose) polymerase; RACE, rapid amplification of cDNA ends; GST, glutathione S-transferase; 3-ABA, 3-aminobenzamide; DBD, DNA binding domain; TK, thymidine kinase. (1Aguiar R.C. Yakushijin Y. Kharbanda S. Salgia R. Fletcher J.A. Shipp M.A. Blood. 2000; 96: 4328-4334Crossref PubMed Google Scholar). In a pilot series of primary DLBCLs, BAL expression was significantly higher in chemoresistant tumors. In our initial report, we also showed that BAL1 encodes a nuclear protein with a duplicated N-terminal domain homologous to the non-histone region of histone macroH2A (2Pehrson J.R. Fried V.A. Science. 1992; 257: 1398-1400Crossref PubMed Scopus (282) Google Scholar). This ≈135-aa non-histone region, which contains a short stretch of basic residues and a putative leucine zipper motif, has been termed a macro domain (3Ladurner A.G. Mol. Cell. 2003; 12: 1-3Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 4Aravind L. Trends Biochem. Sci. 2001; 26: 273-275Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). Several lines of evidence suggest that macro domains may modulate transcription. First, histone macroH2A is enriched in the inactive mammalian X chromosome, potentially implicating the macro domain-containing protein in gene silencing (5Costanzi C. Pehrson J.R. Nature. 1998; 393: 599-601Crossref PubMed Scopus (486) Google Scholar). More specifically, the macro domain of histone macroH2A represses transcription in vitro (6Perche P.Y. Vourc'h C. Konecny L. Souchier C. Robert-Nicoud M. Dimitrov S. Khochbin S. Curr. Biol. 2000; 10: 1531-1534Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar) and directly interferes with transcription factor binding in nucleosomes containing this variant histone (7Angelov D. Molla A. Perche P.Y. Hans F. Cote J. Khochbin S. Bouvet P. Dimitrov S. Mol. Cell. 2003; 11: 1033-1041Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). In addition, the crystallographic structure of a macro domain-only protein (AF1521, from Archaeoglobus fulgidus) includes a known DNA binding motif, further suggesting that macro domains might interact with nucleic acids (8Allen M.D. Buckle A.M. Cordell S.C. Lowe J. Bycroft M. J. Mol. Biol. 2003; 330: 503-511Crossref PubMed Scopus (104) Google Scholar). In addition to containing N-terminal candidate macro domains, the BAL1 protein includes a C-terminal region with homology to the catalytic domain of PARP (poly [ADP-ribose] polymerase) proteins. PARPs catalyze the transfer of ADP-ribose onto acceptor proteins using NAD+ as a substrate (9Ame J.C. Spenlehauer C. de Murcia G. BioEssays. 2004; 26: 882-893Crossref PubMed Scopus (1262) Google Scholar, 10Smith S. Trends Biochem. Sci. 2001; 26: 174-179Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar). The resulting poly(ADP-ribosyl)ation of acceptor proteins has been principally associated with functions of the prototype PARP-1 enzyme and its role in DNA repair (9Ame J.C. Spenlehauer C. de Murcia G. BioEssays. 2004; 26: 882-893Crossref PubMed Scopus (1262) Google Scholar). Recently, other PARP domain-containing proteins have been identified and implicated in additional nuclear processes (11Ju B.G. Solum D. Song E.J. Lee K.J. Rose D.W. Glass C.K. Rosenfeld M.G. Cell. 2004; 119: 815-829Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 12Kim M.Y. Mauro S. Gevry N. Lis J.T. Kraus W.L. Cell. 2004; 119: 803-814Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, 13Tulin A. Spradling A. Science. 2003; 299: 560-562Crossref PubMed Scopus (391) Google Scholar). This diverse group of proteins contains a minimal PARP active site embedded within a larger polypeptide (9Ame J.C. Spenlehauer C. de Murcia G. BioEssays. 2004; 26: 882-893Crossref PubMed Scopus (1262) Google Scholar). In these proteins, termed the PARP superfamily, the functional consequences of PARP activity may be dependent on additional functional domains. For example, the PARP family member, Tankyrase 1, controls telomere physiology via poly(ADP-ribosyl)ation and inhibition of TRF-1, a negative regulator of telomere length (14Smith S. Giriat I. Schmitt A. de Lange T. Science. 1998; 282: 1484-1487Crossref PubMed Scopus (913) Google Scholar). In our initial description of BAL-1, we noted homology between the BAL-1 C terminus and the Tankyrase 1 PARP-like catalytic domain (1Aguiar R.C. Yakushijin Y. Kharbanda S. Salgia R. Fletcher J.A. Shipp M.A. Blood. 2000; 96: 4328-4334Crossref PubMed Google Scholar). However, BAL-1 did not exhibit PARP-like activity in preliminary functional assays. More recently, we identified additional BAL family members with potential critical differences in their C-terminal PARP-like regions. Given the emerging evidence that PARP family proteins represent possible cancer treatment targets (15Seimiya H. Muramatsu Y. Ohishi T. Tsuruo T. Cancer Cell. 2005; 7: 25-37Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 16Farmer H. McCabe N. Lord C.J. Tutt A.N. Johnson D.A. Richardson T.B. Santarosa M. Dillon K.J. Hickson I. Knights C. Martin N.M. Jackson S.P. Smith G.C. Ashworth A. Nature. 2005; 434: 917-921Crossref PubMed Scopus (4930) Google Scholar, 17Bryant H.E. Schultz N. Thomas H.D. Parker K.M. Flower D. Lopez E. Kyle S. Meuth M. Curtin N.J. Helleday T. Nature. 2005; 434: 913-917Crossref PubMed Scopus (3842) Google Scholar) and the reported association between BAL-1 expression and chemoresistance in DLBCL, we performed detailed structure/function analyses of BAL family members. Cloning and Chromosomal Localization of BAL2 and BAL3—BAL1 cDNA and protein sequences were used to search human nucleotide and protein databases (www.ncbi.nlm.nih.gov/BLAST). Candidate homologue genes were further characterized by and For from and lines were with a and to of amplification as described R.C. Yakushijin Y. Kharbanda S. S. Shipp M.A. Blood. PubMed Google Scholar). the from and lines were also used for with from the identified and the of BAL2 and BAL3, we the human with these gene these we a series of and with DNA from these was and was performed as described R.C. A. S. M. A. J. A. Blood. PubMed Google Scholar). of BAL or C-terminal domains of proteins were in for of critical residues using the were also as and the from the the length of of the between The the and for in is by in to the by sequences directly for that is not the of the of the and for a is not PARP putative C-terminal PARP catalytic domains of the BAL family proteins were to and the proteins using the expression activity were as described (14Smith S. Giriat I. Schmitt A. de Lange T. Science. 1998; 282: 1484-1487Crossref PubMed Scopus (913) Google Scholar, F. M. de Murcia G. J. Biol. Full Text PDF PubMed Google Scholar). of BAL proteins or of high PARP protein as a were for in containing and with or of DNA In was of NAD+ as substrate in assays. In the PARP was 1 were by the addition of proteins were in in and by In proteins were by and to For the proteins were to and with a to poly(ADP-ribose) were in containing For these human were on 1 1 were with of including of the report of the specific and of as described (6Perche P.Y. Vourc'h C. Konecny L. Souchier C. Robert-Nicoud M. Dimitrov S. Khochbin S. Curr. Biol. 2000; 10: 1531-1534Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). The were by and the DNA binding domain to BAL1 BAL1 terminus including the macro domains BAL1 terminus macro domains and PARP domain these were with amino acids of protein in a domain of as a The as as the were of and were described (6Perche P.Y. Vourc'h C. Konecny L. Souchier C. Robert-Nicoud M. Dimitrov S. Khochbin S. Curr. Biol. 2000; 10: 1531-1534Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). were by were and were using the and enzyme The activity from was used as for were performed in In the of DNA were by of with that proteins were not The BAL of identified additional conserved suggesting that BAL1 is a of a larger gene family (1Aguiar R.C. Yakushijin Y. Kharbanda S. Salgia R. Fletcher J.A. Shipp M.A. Blood. 2000; 96: 4328-4334Crossref PubMed Google Scholar). For this we used BAL1 cDNA and protein sequences to search human and protein databases and two genes termed BAL2 and BAL2 to the characterized (1Aguiar R.C. Yakushijin Y. Kharbanda S. Salgia R. Fletcher J.A. Shipp M.A. Blood. 2000; 96: 4328-4334Crossref PubMed Google Scholar). we identified additional BAL2 a that is the described terminus on However, the BAL2 cDNA lacks of the the that BAL2 encodes a protein with additional N-terminal The of BAL2 and with this not Of interest, BAL2 includes N-terminal macro domains In addition, we used to the of BAL2 and that or unique C and and encodes a protein containing a putative PARP catalytic lacks these suggesting that these C-terminal differences might be In of human we of BAL1 and BAL2 expression with the in and and the in not and R.C. Yakushijin Y. Kharbanda S. Salgia R. Fletcher J.A. Shipp M.A. Blood. 2000; 96: 4328-4334Crossref PubMed Google Scholar). additional group of characterized cDNA were identified that did not to BAL2 for protein to these sequences were of which a protein termed 1) The terminus is that of the protein by However, are sequences the of BAL3, of is and the expression of in human was to be to that of BAL1 and BAL2 not BAL1 was to (1Aguiar R.C. Yakushijin Y. Kharbanda S. Salgia R. Fletcher J.A. Shipp M.A. Blood. 2000; 96: 4328-4334Crossref PubMed Google Scholar). the human with the BAL2 and -3 cDNA we that these genes also to In the genes are in within the that are were by amplification of to this region not BAL2 and BAL3, but BAL1, PARP BAL family members have C that sequences with to the PARP-1 catalytic domain 1 and The putative PARP active site minimal PARP-1 catalytic (9Ame J.C. Spenlehauer C. de Murcia G. BioEssays. 2004; 26: 882-893Crossref PubMed Scopus (1262) Google Scholar) of and is to that of the prototype and to that of PARP family member, Tankyrase 1 (14Smith S. Giriat I. Schmitt A. de Lange T. Science. 1998; 282: 1484-1487Crossref PubMed Scopus (913) Google Scholar) Of and are their PARP active these sequences also the catalytic in and in and additional conserved donor and acceptor sites S. Trends Biochem. Sci. 2001; 26: 174-179Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, A. Spenlehauer C. H. Murcia J. M. F. M. M. Murcia G. J. Sci. 2003; PubMed Scopus Google Scholar, A. de Murcia G. J. Mol. Biol. 1998; PubMed Scopus Google Scholar, A. de Murcia G. 1998; PubMed Scopus Google Scholar). In the BAL1 C terminus is only with the PARP-1 catalytic domain; in addition, this BAL-1 lacks the catalytic in and additional donor and acceptor sites conserved in and -3 and analyses of the and between these PARP active sites that the BAL1 is to that of BAL2 and that of PARP-1 or Tankyrase 1 and of the BAL family members exhibit PARP we BAL1, and C for in PARP functional (8Allen M.D. Buckle A.M. Cordell S.C. Lowe J. Bycroft M. J. Mol. Biol. 2003; 330: 503-511Crossref PubMed Scopus (104) Google Scholar, 13Tulin A. Spradling A. Science. 2003; 299: 560-562Crossref PubMed Scopus (391) Google Scholar). In these PARP-1 was as a the ability of these proteins to ADP-ribose to protein using as a of the to that of BAL1, and were used in these The C-terminal domains of and BAL3, but not BAL1, were of of the 3-ABA, the of and the of these In with and but not BAL1, were also identified with poly(ADP-ribose) The of BAL3, and PARP-1 was by 3-ABA, the of the Of interest, the PARP activity of was the of DNA in the did not the of PARP-1 activity The BAL N-terminal Macro and and -3 N-terminal sequences with homology to described macro domains 1 and BAL1 and sequences two macro domains, BAL2 and regions 1 and macro domains are to the macro by in and described as the domain domains and However, the the macro domains from to of the and of BAL macro domains specific and and the macro domains of BAL1 and BAL2 the macro domain of BAL2 and the of and the macro domain of BAL2 with the macro domain of is to the the macro domain of BAL1 from the suggest that the macro domains within a BAL protein might have functional that are conserved in BAL proteins. The Macro of the human the of additional human genes macro domain proteins of these genes are the characterized and histone and the of this family (2Pehrson J.R. Fried V.A. Science. 1992; 257: 1398-1400Crossref PubMed Scopus (282) Google is as two and 1 and The described histone C. Pehrson J.R. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. 2001; 10: PubMed Scopus (145) Google Scholar) encodes a protein that is to is known the other human genes macro domain proteins, and The which are conserved from to high have been implicated in H. T. T. T. S. J. PubMed Scopus Google Scholar) and of L. Song M. 2003; 10: PubMed Scopus Google Scholar). was as of a human cDNA and not have In are human genes proteins with macro domains. structural and functional as the of histone or PARP domains, specific gene macroH2A and and is by the of their macro domains Of BAL family members are the only known genes with macro domains in the protein The BAL of the Macro the described association of the macro domain of histone macroH2A with (6Perche P.Y. Vourc'h C. Konecny L. Souchier C. Robert-Nicoud M. Dimitrov S. Khochbin S. Curr. Biol. 2000; 10: 1531-1534Abstract Full Text Full Text PDF PubMed Scopus (100) Google we the that the prototype BAL family member, BAL1, might have a we the ability of BAL1 to repress transcription when tethered a DNA binding to the thymidine This which is used to the activity of proteins, the of the macro domain of histone (6Perche P.Y. Vourc'h C. Konecny L. Souchier C. Robert-Nicoud M. Dimitrov S. Khochbin S. Curr. Biol. 2000; 10: 1531-1534Abstract Full Text Full Text PDF PubMed Scopus (100) Google of of the BAL1 and proteins, and The were to the of the transcription to the histone domain of as a The contains of the site from the transcription by reported M. N. M. J. J. Mol. Cell. Biol. PubMed Scopus Google the activity of the by transcription in a and to of or of are as the activity by domain The BAL1 terminus which lacks the macro domains, on activity. In the N-terminal including macro domains and the BAL1 protein were in transcription. of transcription was significantly in transcription to the PARP activity of the were and performed in are The activity as described M. N. M. J. J. Mol. Cell. Biol. PubMed Scopus Google Scholar) and For this we used a to assess activity of with that of with A. Spenlehauer C. H. Murcia J. M. F. M. M. Murcia G. J. Sci. 2003; PubMed Scopus Google Scholar). transcription in a the of transcription was to that reported for the macro domain of histone macroH2A (6Perche P.Y. Vourc'h C. Konecny L. Souchier C. Robert-Nicoud M. Dimitrov S. Khochbin S. Curr. Biol. 2000; 10: 1531-1534Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). the role of BAL1 macro domains in the additional series of BAL1 was terminus and terminus including macro domains a BAL1 terminus which lacks the macro domains on activity In the macro domain-containing BAL1 terminus and the BAL1 protein were in transcription transcription was not as were using the not In addition, the proteins did not repress the activity of or which the sites not that was to association with the PARP and BAL1 which represses transcription via its N-terminal macro lacks C-terminal PARP activity. However, BAL2 and -3 macro domains and active PARP of the known association between PARP-1 function and active chromatin (9Ame J.C. Spenlehauer C. de Murcia G. BioEssays. 2004; 26: 882-893Crossref PubMed Scopus (1262) Google Scholar, B.G. Solum D. Song E.J. Lee K.J. Rose D.W. Glass C.K. Rosenfeld M.G. Cell. 2004; 119: 815-829Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 12Kim M.Y. Mauro S. Gevry N. Lis J.T. Kraus W.L. Cell. 2004; 119: 803-814Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, 13Tulin A. Spradling A. Science. 2003; 299: 560-562Crossref PubMed Scopus (391) Google Scholar). For these we also the ability of and the N-terminal macro domain to repress transcription was significantly BAL1 in transcription to the PARP activity of The BAL gene family is of members in on BAL proteins have N-terminal macro domains of transcription and also exhibit PARP activity. The macro domain is conserved of amino acids described as the non-histone region of the variant histone macroH2A (2Pehrson J.R. Fried V.A. Science. 1992; 257: 1398-1400Crossref PubMed Scopus (282) Google Scholar). proteins of the macro domain in in other this is embedded within larger and associated with a of as histone domain in the macroH2A the PARP domain in the BAL and the region putative binding in In our genome-wide we identified human macro domains by unique genes including the BAL family members. BAL macro domains have the and the that the two or macro domains within a BAL protein not with with macro domains in other BAL family members. This structural the of specific macro regions in BAL proteins, functional differences between these macro with this suggest that the macro domains in macroH2A and macro in their ability to G. M. C. A.G. Mol. Biol. 2005; 12: PubMed Scopus Google Scholar). has been the role of the macro domains is macroH2A is enriched on the inactive mammalian X (5Costanzi C. Pehrson J.R. Nature. 1998; 393: 599-601Crossref PubMed Scopus (486) Google and the macro domain from this variant histone represses transcription in vitro (6Perche P.Y. Vourc'h C. Konecny L. Souchier C. Robert-Nicoud M. Dimitrov S. Khochbin S. Curr. Biol. 2000; 10: 1531-1534Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). was for the of histone (7Angelov D. Molla A. Perche P.Y. Hans F. Cote J. Khochbin S. Bouvet P. Dimitrov S. Mol. Cell. 2003; 11: 1033-1041Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). The macro domain of histone macroH2A in a positioned was to with transcription factor the histone region This was further by crystallographic that identified between macro domains and DNA binding (8Allen M.D. Buckle A.M. Cordell S.C. Lowe J. Bycroft M. J. Mol. Biol. 2003; 330: 503-511Crossref PubMed Scopus (104) Google Scholar). also suggest that macro domains may or ADP-ribose G. M. C. A.G. Mol. Biol. 2005; 12: PubMed Scopus Google Scholar, G. M.D. C. F. Bycroft M. A.G. J. 2005; PubMed Scopus Google Scholar). the functional consequences of these to be are of the PARP activity of and In our the BAL N-terminal macro domain transcription when the of a promoter. The of BAL macro was to that with the macro domains of histone macroH2A (6Perche P.Y. Vourc'h C. Konecny L. Souchier C. Robert-Nicoud M. Dimitrov S. Khochbin S. Curr. Biol. 2000; 10: 1531-1534Abstract Full Text Full Text PDF PubMed Scopus (100) Google the functional between macro domains from proteins. histone BAL proteins may the of transcription and to specific chromatin regions (8Allen M.D. Buckle A.M. Cordell S.C. Lowe J. Bycroft M. J. Mol. Biol. 2003; 330: 503-511Crossref PubMed Scopus (104) Google Scholar). The macro domains of and -3 might also as to direct and -3 PARP activity to in the In our in vitro BAL family members with functional PARP domains significantly transcription suggesting that BAL activity is by family macro domains and PARP sites. In this is of that active or inactive PARP-1 have on transcription (9Ame J.C. Spenlehauer C. de Murcia G. BioEssays. 2004; 26: 882-893Crossref PubMed Scopus (1262) Google Scholar, B.G. Solum D. Song E.J. Lee K.J. Rose D.W. Glass C.K. Rosenfeld M.G. Cell. 2004; 119: 815-829Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 12Kim M.Y. Mauro S. Gevry N. Lis J.T. Kraus W.L. Cell. 2004; 119: 803-814Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, 13Tulin A. Spradling A. Science. 2003; 299: 560-562Crossref PubMed Scopus (391) Google Scholar). is not BAL proteins modulate transcription or in association with a However, the identified role of in transcription M. Mol. Biol. 2003; PubMed Scopus Google is of that BAL1 to and a family with activity R.C. L. C. J.C. Shipp M.A. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) on C-terminal BAL proteins were to be members of the PARP and termed and (9Ame J.C. Spenlehauer C. de Murcia G. BioEssays. 2004; 26: 882-893Crossref PubMed Scopus (1262) Google Scholar). However, several residues critical for PARP catalytic and are in BAL1, including of PARP-1 A. de Murcia G. J. Mol. Biol. 1998; PubMed Scopus Google Scholar, A. de Murcia G. 1998; PubMed Scopus Google Scholar, M. Murcia J. de Murcia G. PubMed Scopus Google Scholar, A. de Murcia J. de Murcia G. Sci. S. A. PubMed Scopus (227) Google Scholar). with these structural BAL1 lacks PARP and -3 exhibit poly(ADP-ribose) polymerase activity. and -3 have PARP active sites and a higher of with the prototype PARP-1 catalytic of the identified acceptor and donor sites A. Spenlehauer C. H. Murcia J. M. F. M. M. Murcia G. J. Sci. 2003; PubMed Scopus Google Scholar) is in these BAL family members. suggest that the for a functional PARP domain might be that and are of in a In PARP-1 and as a that the of these their specific targets (9Ame J.C. Spenlehauer C. de Murcia G. BioEssays. 2004; 26: 882-893Crossref PubMed Scopus (1262) Google Scholar, S. de Lange T. Curr. Biol. 2000; 10: Full Text Full Text PDF PubMed Scopus Google Scholar). is that of the BAL proteins a of additional BAL binding and putative targets for this post-translational modification the role of poly(ADP-ribosyl)ation in also PARP activity in nuclear processes that chromatin configuration and transcription (11Ju B.G. Solum D. Song E.J. Lee K.J. Rose D.W. Glass C.K. Rosenfeld M.G. Cell. 2004; 119: 815-829Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 12Kim M.Y. Mauro S. Gevry N. Lis J.T. Kraus W.L. Cell. 2004; 119: 803-814Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, 13Tulin A. Spradling A. Science. 2003; 299: 560-562Crossref PubMed Scopus (391) Google Scholar). In these to association between active PARP-1 and high transcription activity via of chromatin A. Spradling A. Science. 2003; 299: 560-562Crossref PubMed Scopus (391) Google poly(ADP-ribosyl)ation of (11Ju B.G. Solum D. Song E.J. Lee K.J. Rose D.W. Glass C.K. Rosenfeld M.G. Cell. 2004; 119: 815-829Abstract Full Text Full Text PDF PubMed Scopus (250) Google or M.Y. Mauro S. Gevry N. Lis J.T. Kraus W.L. Cell. 2004; 119: 803-814Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar). by binding to the M.Y. Mauro S. Gevry N. Lis J.T. Kraus W.L. Cell. 2004; 119: 803-814Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar) or (11Ju B.G. Solum D. Song E.J. Lee K.J. Rose D.W. Glass C.K. Rosenfeld M.G. Cell. 2004; 119: 815-829Abstract Full Text Full Text PDF PubMed Scopus (250) Google inactive PARP-1 a structural role that gene and the suggest a the transcription by N-terminal of the BAL proteins might be by C-terminal PARP activity via poly(ADP-ribosyl)ation of poly(ADP-ribosyl)ation might be the primary functional of the and proteins, and the macro domains the critical with specific of the The noted differences between BAL1 and the to these and to the to BAL PARP activity in Given emerging evidence that PARP proteins represent possible cancer treatment targets (15Seimiya H. Muramatsu Y. Ohishi T. Tsuruo T. Cancer Cell. 2005; 7: 25-37Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 16Farmer H. McCabe N. Lord C.J. Tutt A.N. Johnson D.A. Richardson T.B. Santarosa M. Dillon K.J. Hickson I. Knights C. Martin N.M. Jackson S.P. Smith G.C. Ashworth A. Nature. 2005; 434: 917-921Crossref PubMed Scopus (4930) Google Scholar, 17Bryant H.E. Schultz N. Thomas H.D. Parker K.M. Flower D. Lopez E. Kyle S. Meuth M. Curtin N.J. Helleday T. Nature. 2005; 434: 913-917Crossref PubMed Scopus (3842) Google functional of BAL family members may have in lymphoma. Smith for PARP activity assays.