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HISTONE JUN DIMERIZATION 2 (JDP2): ROLE IN CELLULAR AND AGING

Yu-Chang Huang,1 Shigeo Saito1,2 and Kazunari Kzaushige Yokoyama1,3,4 1Center of Excellence for Environmental Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Saito Laboratory of Technology, Yaita, Tochigi, 3Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, and 4Gene Engineering Division, RIKEN BioResource Center, Koyadai, Tsukuba, Ibaraki, Japan.

Transcription factor 2 (JDP2) binds directly to and DNA, and inhibits p300-mediated of core histones and reconstituted that contain JDP2-recognition DNA sequences. The region of JDP2 that encompasses its -binding domain and DNA-binding region is essential to inhibit histone acetylation by histone acetyltransferases. Moreover, assays of assembly in vitro demonstrate that JDP2 also has histone-chaperone activity. The of the region responsible for inhibition of histone acetyltransferase activity within JDP2 eliminates repression of from the c-jun by JDP2, as well as JDP2-mediated inhibition of retinoic-acid-induced differentiation. Thus JDP2 plays a key role as a of cell differentiation by regulating the expression of with an protein 1 (AP-1) site via inhibition of histone acetylation and/or assembly and disassembly of nucleosomes. Senescent cells show a series of alterations, including flatten and enlarged morphology, increase in nonspecific acidic β-galactosidase activity, condensation, and changes in expres- sion patterns. The onset and maintenance of senescence are regulated by two tumor suppressors, and . The expression of p53 and retinoblastoma proteins is regulated by two distinct proteins, p16Ink4a and Arf, respectively, which are encoded by . JDP2 inhibits recruitment of the polycomb repressive complexes 1 and 2 (PRC-1 and PRC-2) to the promoter of the gene that encodes p16Ink4a and inhibits the of 27 of (H3K27). The PRCs associate with the p16Ink4a/Arf in young proliferating cells and dissociate from it in senescent cells. Therefore, it seems that chromatin-remodeling factors that regulate association and dissoci- ation of PRCs, and are controlled by JDP2, might play an important role in the senescence program. The molecular mechanisms that underlie the action of JDP2 in cellular aging and replicative senescence by mediating the dissociation of PRCs from the p16Ink4a/Arf locus are discussed.

Key Words: Arf, Jun dimerization protein 2, p16Ink4a, polycomb repressive complex, replicative senescence (Kaohsiung J Med Sci 2010;26:515–31)

The structure of chromatin, which influences numerous DNA-associated phenomena, such as transcription, re- plication, recombination and repair, is controlled by a Received: Jun 2, 2010 Accepted: Jun 22, 2010 complex combination of histone modifications, ATP- Address correspondence and reprint requests to: Dr Kazunari Kzaushige Yokoyama, Center of dependent chromatin-remodeling , and nucle- Excellence for Environmental Medicine, Graduate osome-assembly factors. The modification of histones Institute of Medicine, Kaohsiung Medical occurs at their N-terminal tails, which can be modified University, 100 Shih-Chuan 1st Road, San Ming District, 807 Kaohsiung, Taiwan. by acetylation, , methylation, ubiq- E-mail: [email protected] uitination, sumoylation, and ADP-ribosylation [1,2].

Kaohsiung J Med Sci October 2010 • Vol 26 • No 10 515 © 2010 Elsevier. All rights reserved. Y.C. Huang, S. Saito, and K.K. Yokoyama

Among these modifications, the acetylation of histones not only by cellular aging, but also by the forced occurs at highest frequency and has been studied most activation of the -activated protein (MAP) extensively, with the resultant identification of a num- pathway and by genotoxic stressors, such as ber of histone acetyltransferases (HATs) and histone hydrogen peroxide and certain DNA-damaging com- deacetylases (HDACs), together with their target lysine pounds. Senescence increases the activities of two well- residues within specific histones in the chromatin. The known tumor suppressors, (Rb) activities of HATs are not only antagonized by HDACs and p53 protein. The expression of Rb and p53 is regu- but are also regulated by cellular and viral regulatory lated by two distinct proteins, p16Ink4a and Arf, respec- factors that include histone chaperones and enzymes tively, which are encoded by the cdkn2a locus [17]. that catalyze posttranslational modification [3,4]. The expression of p16Ink4a increases dramatically with Chromatin consists of structural units known as increasing numbers of cell divisions in primary fibro- nucleosomes. Each nucleosome consists of two histone blasts in culture, and in rodent and human models

H2A–H2B dimers, a histone (H3–H4)2 tetramer, and in vivo. In this review, we summarize the roles of DNA that is wrapped around the resultant histone p16Ink4a and Arf in the , and describe a novel octamers. During chromatin assembly, a histone mechanism for the regulation of their expression.

(H3–H4)2 tetramer is formed before the two hetero- dimers H2A and H2B are incorporated to form a nucleo- some [5,6]. Regulation of transcription is associated with P16INK4A AND THE RB PATHWAY alterations in chromatin structure that include histone modifications and changes in nucleosome structure Genes that are essential for cell-cycle progression are [7–10]. Compaction of the chromatin and organization transcribed at the beginning of by the of nucleosomes represent a barrier that has to be over- family of transcription factors. E2F is controlled by the come prior to activation of transcription. The N-terminal Rb family of proteins, pRb, p107, and p130 [18,19]. histone tails that protrude from the nucleosomes do not Early in G1, unphosphorylated Rb proteins bind to play a significant role in nucleosome formation, but they the E2F family of proteins and inactivate their func- appear to act as docking sites for other proteins and pro- tion [20,21]. During G1, the Rb proteins are inacti- tein complexes to regulate chromatin compaction [9]. vated by phosphorylation by dependent kinase The structure of chromatin changes to allow greater 4/6 (Cdk4/6)– complexes, thereby allowing accessibility by transcription factors when a gene is the transcription of E2F-dependent genes, including to be activated [9]. It has been suggested that the . Upregulated cyclin E forms a complex with change to a more accessible state not only involves the cdk2 that mediates the hyperphosphorylation of the modification of histones and alterations in nucleoso- Rb proteins, which is an essential requirement for mal arrays, but also results from changes in nucleo- G1/S transition. p16Ink4a is an allosteric inhibitor of some integrity that are due to displacement of histones cdk4/6. Binding to p16Ink4a changes the conformations [11]. Furthermore, it has been demonstrated that his- of cdk4/6, which prevents its interaction with cyclin D tone chaperones play a critical role in these processes [22,23]. Therefore, p16Ink4a acts as an inhibitor of the cell [12–15]. Thus it is tempting to speculate that histone cycle at G1 by modulating the Rb pathway. p16Ink4a is chaperones might be important for the compaction often lost in a variety of human malignancies, includ- of chromatin, and it is now important to determine ing , , and pancreatic adenocar- whether certain co- of transcription might cinoma [24]. In contrast, the upregulation of p16Ink4a influence the deposition and assembly of nucleosomes induces cell-cycle arrest and senescence [23,24]. via regulation of histone-chaperone activity. Primary cultures of untransformed cells stop growing after several weeks and undergo senescence, ARF AND THE P53 PATHWAY a phenomenon that is related to so-called cellular aging. Senescence protects normal cells from abnor- p53 is known to mediate cell-cycle arrest in G1 and G2, mal growth signals and oncogenic transformation, and and . A number of downstream targets of p53 impairs their reprogramming to pluripotent stem cells are involved in these processes, including p21Cip/waf1 [16] by interrupting the cell cycle. Senescence is induced in G1 arrest [25], 14-3-3 sigma and growth arrest and

516 Kaohsiung J Med Sci October 2010 • Vol 26 • No 10 Control of senescence by JDP2

DNA damage inducer gene 45 (GADD45) in G2 arrest the cell cycle is not arrested by a senescence program, [26,27], and , Bax, PI-3 up-regulation modulator the CpG islands in the p16Ink4a promoter and 1 are of apoptosis (PUMA), Fas/Apo1, and Killer/DR5 in methylated and the p16Ink4a gene is silenced [49,50]. apoptosis [28–32]. p53 is regulated at the levels of pro- Understanding the role of all the factors that regu- tein stability and activity, and to some extent at tran- late the expression of p16Ink4a is important in clarifying scription and translation [33,34]. In unstressed cells, the molecular mechanism of cellular aging. We describe p53 protein levels are very low because its degrada- here some of these factors, including transcriptional tion is mediated by the E3 ligase activity of activators and inhibitors, and epigenetic regulators. murine double minute 2 (), which targets p53 for ubiquitin-dependent proteolysis [35]. MDM2 is a Transcriptional activators transcriptional target of p53, therefore, p53 directly Both Ets1 and Ets2 activate p16Ink4a expression through activates expression of its own negative regulator, activation of the Ras-MEK-MAP kinase pathway by which produces a potent negative feedback regulatory directly binding to the ETS consensus sites in its pro- loop [36]. There are several stress-responsive , moter [47]. In human fibroblasts, the hyperactivation which, by phosphorylating p53, inhibit p53 degrada- of Ets2 by overexpression of the Ras induces tion by MDM2 and increase its transcriptional activ- G1 arrest, premature senescence, and increased expres- ity [37–39]. DNA damage rapidly activates the ataxia sion of p16Ink4a. Ets2 seems to be the main regulator telangiectasia mutated and ataxia telangiectasia related of p16Ink4a expression during oncogenic premature proteins, which phosphorylate the checkpoint kinases senescence, whereas Ets1 plays a role in replicative 1 and 2 (Chk1 and Chk2), which in turn propagate the senescence [51,52]. The basic helix-loop-helix (b-HLH) signal to downstream effectors such as p53 [40,41]. protein E47 binds to DNA and proteins through its Chk1 and Chk2 phosphorylate p53 at Ser 20, which basic and HLH domains, respectively. The E47 homod- prevents the efficient recruitment of MDM2. Thus imer binds specifically to the E box (CANNTG) in the p53 is stabilized and its expression level is increased p16Ink4a promoter [46]. Overexpression of E47 inhibits in response to stress signaling. Arf is predominantly the proliferation of some tumor cell lines by inducing localized in the nucleoli and is stabilized by binding expression of p16Ink4a. Inhibition of E47 by RNA inter- to nucleophosmin. In response to stress signaling, Arf ference significantly reduces expression of p16Ink4a is released from nucleophosmin and translocates to and delays the onset of senescence [44]. Similarly, the the nucleoplasm, where it interacts with MDM2, heterodimerization of E47 with ectopically expressed inhibits its E3 activity, and blocks the Tal1 inhibits expression of p16Ink4a [53]. nucleocytoplasmic shuttling of the MDM2–p53 com- plex. Therefore, the consequences of the activation of Transcriptional inhibitors Arf are stabilization and activation of p53 [42,43]. The expression of inhibition of differentiation protein-1 (Id-1) correlates negatively with p16Ink4a expression during the process of senescence [44,47]. The expres- TRANSCRIPTIONAL REGULATION OF P16INK4A sion of p16Ink4a in mouse embryonic fibroblasts (MEFs) is higher in those from Id-1-deficient mice than in The transcriptional regulation of the p16Ink4a gene is an wild-type MEFs [38]. Overexpression of Id-1 delays important event in . Expression of replicative senescence by inhibiting p16Ink4a in human p16Ink4a is increased during replicative senescence and keratinocytes and endothelial cells [54,55]. Id-1 does in the premature senescence induced by oncogenic not have a basic DNA-binding domain, unlike the activation. Its expression is regulated by transcriptional b-HLH protein E47. Instead, Id-1 inhibits transcrip- activators such as Ets1/2 and the basic helix-loop-helix tion of p16Ink4a by heterodimerization with Ets2 [47]. (b-HLH) protein E47, as well as by transcriptional Id-1 also heterodimerizes with E47, and inhibits its inhibitors including the Id-1 HLH protein [44–47]. The transcriptional activity [56]. p16Ink4a locus is also epigenetically repressed by the polycomb repressive complexes 1 and 2 (PCR-1 and Epigenetic regulators PCR-2, respectively), which methylate lysine 27 of his- The p16Ink4a locus is also regulated epigenetically. The tone H3 (H3K27) [48]. In transformed cells, in which locus is transcriptionally silenced by the trimethylation

Kaohsiung J Med Sci October 2010 • Vol 26 • No 10 517 Y.C. Huang, S. Saito, and K.K. Yokoyama of lysine 27 of histone H3 (H3K27) in young proli- An important aim is to understand how the H3K27 ferating primary cells. In contrast, the expression of trimethylation signal is lost in senescent cells. The pos- p16Ink4a increases in aged and senescent cells with the sible explanations are as follows: (1) the action of as-yet- loss of H3K27 trimethylation [57]. Methylation of unidentified histone demethylases and/or inhibitors H3K27 and silencing of the p16Ink4a locus are medi- of the methyl transferases involved in H3K27 trimethy- ated by PRC1 and PRC2. PRC1 contains a number lation; or (2) histone chaperones recruit histone vari- of subunits, including polycomb (CBX2, 4, 6, 7 or 8 in ants to the chromatin to alter . A recent humans), polyhomeotic (PH1 or PH2 in humans), study has shown that the H3K27-specific demethy- B lymphocyte molony murine insertion lase, Junonji domain-containing protein 3 (JMJD3) is region 1 homology (Bmi1), Ring1B, and other sub- induced by Ras–Raf signaling, as well as by environ- units [58], whereas PRC2 is composed of enhancer of mental stresses. JMJD3 is recruited to the p16Ink4a locus Zeste 2 (Ezh2), suppressor of Zeste 12 protein homolog and contributes to the transcriptional activation of (Suz12), and embryonic ectoderm development (Eed) p16Ink4a [74,75]. We propose that senescence is regu- subunits [48,59]. In PRC2, Ezh2 is the catalytic subunit lated by Jun dimerization protein 2 (JDP2) of p16Ink4a, that methylates H3K27 [48], whereas the other com- which has histone-binding and chaperone activities ponents are indispensible for the function of the com- [74,75]. JDP2 is a member of the activator protein 1 plex. Suz12 is essential for complex formation and (AP1) family of transcription factors, and activates di- and trimethylation of H3K27 in vivo [60,61]. In con- the transcription of p16Ink4a, as described below [76]. trast, Eed is required for global H3K27 methylation, including its monomethylation [62]. PRC1, the CBX subunit recognizes and binds to trimethylated H3K27 REGULATION OF ARF [63,64]. Ring1B has E3 ligase activity for the ubiquity- lation of histone H2A, whereas Bmi1 acts as a cofactor The contribution of Arf to senescence is still controver- [65,66]. Ubiquitylation of H2A by PRC1 prevents sial. In general, it seems that p16Ink4a plays a central transcript elongation by RNA polymerase II [67]. role in senescence and tumor suppression in human PRC1 has been shown by electron microscopy to cells, whereas Arf has a relatively more prominent role contribute to chromatin compaction [68]. Therefore, in mouse cells. In human cells, are specifi- a possible molecular mechanism of PRC-mediated cally found in p16Ink4a, rather than in Arf. Mutations of gene silencing might involve trimethylation of histone p16Ink4a are frequently observed in primary , H3K27 by Ezh2 and the other subunits of PRC2. Then, and occur during the establishment of immortal cell this acts as a binding site for PRC1, which ubiquitylates lines [24,77]. Signaling by the Ras oncogene and telom- H2A and compacts the chromatin, and leads to inhi- ere shortening also induce p53- and Arf-independent bition of transcript elongation by RNA polymerase II. growth arrest [78,79]. In contrast, in MEFs, expression PRCs might also inhibit earlier steps in transcrip- of Arf correlates with the onset of senescence, and cells tion, because PRC1 interacts with components of the that lack Arf do not become senescent in culture [80,81]. basal transcription machinery, the TATA-box-binding Mouse strains with targeted deletions in p16Ink4a or protein-associated factors [69,70]. This inhibition does Arf are tumor prone, whereas animals that lack p16Ink4a not appear to involve blocking the access of RNA poly- and Arf have a more severe phenotype [53,81–84]. merase to the promoter, because the PRCs and tran- Signaling from oncogenic Ras activates transcription of scription factors bind to the target genes at the same the cyclin-D-binding Myb-like protein 1 gene (Dmp1) time [68,70–73]. In summary, p16Ink4a transcription is via the MAP kinase pathway and AP1 transcription inhibited by PRC2, which methylates histone H3K27, factors, such as c-Jun and Jun-B. DMP1 binds to and which in turn recruits PRC1. PRC1 represses p16Ink4a activates transcription of the Arf promoter [85]. This expression in young proliferating cells. In aged and pathway is important, because oncogenic Ras fails to stressed cells, H3K27 trimethylation markers of PRC1 activate Arf in MEFs from Dmp1-null mice [86]. are lost and PRC1 dissociates from the p16Ink4a locus, Curiously, factors that activate Arf expression can which results in transcriptional activation of p16Ink4a have different phenotypic effects: Ras induces sen- by Ets1 and/or Ets2, and the entry of the cells into escence, whereas induces apoptosis. The over- senescence. expression of Myc in B lymphocytes augments cell

518 Kaohsiung J Med Sci October 2010 • Vol 26 • No 10 Control of senescence by JDP2 proliferation, which is counteracted by the Arf–p53– contributions of these factors to senescence seem to MDM2 pathway. Suppression of this pathway inhibits differ in humans and mice. Cultured mouse fibrob- Myc-induced apoptosis and facilitates formation of lasts undergo senescence even when they have long B-cell lymphoma [87]. However, another study has telomeres and high activity. Senescence is shown that induction of Arf requires high and con- abrogated by the loss of the p16Ink4a/Arf locus [82]. In tinuous Myc activity, and that physiological levels of human cell cultures, the ectopic expression of telom- Myc are insufficient to stimulate the Arf promoter [88]. erase is sufficient to overcome senescence by main- taining the length of the telomeres [97]. In mice, the maintenance of telomere length is important because E2F TRANSCRIPTION FACTORS ACTIVATE telomerase deficiency shortens their lifespan and THE ARF PROMOTER leads to premature aging [98–100]. The age-dependent accumulation of INK4A has been observed in human stimulates expression of Arf and activates the kidneys and skin [101,102], as well as in the majority Arf–p53–p21WAF1 axis, which blocks . of mouse tissues [100,103]. In oncogene-induced senes- This block is removed by the loss of function of the cence, there is in vivo evidence that Arf is the impor- Arf–MDM2–p53 pathway, which results in E2F1- tant factor in the activation of p53 tumor suppression induced S-phase entry [89]. [103,104]. However, another study has shown that E2F family members bind directly to the Arf pro- components of the DNA-damage signaling cascade, moter, as shown by chromatin immunoprecipitation including ataxia telangiectasia mutated (Atm) and Chk2 assay [90–92]. Ectopic expression of E2F1, and proteins, are crucial for activation of p53 in response activates the Arf promoter in human cells [90)] to oncogenic signals [105–107]. These differences In contrast, an isoform of E2F3, E2F3b, represses the between humans and mice could be attributable to Arf promoter in MEFs [91]. Among the AP1 family species specificity and/or experimental conditions. of transcription factors, the c-Jun- and Fos-related Cellular senescence appears to be related to organism antigen-1 (Fra1) heterodimer is an activator of Arf aging because the same processes appear to be in- transcription in human and mouse cells. The knock- volved. Genetic variants of the p16Ink4a/Arf locus are down of Fos-related antigen-1 in human cells or a linked to age-associated disorders, such as general deficiency of c-Jun in MEFs results in reduced expres- frailty, heart failure, and type 2 diabetes [108–113]. sion of Arf [93]. In contrast, JunD seems to be a repres- Mutations in telomerase or proteins that affect telom- sor of Arf, because MEFs that lack JunD express erase activity are linked to premature human aging syn- elevated levels of Arf, and display p53-dependent dromes, including congenital dyskeratosis and aplastic growth arrest and premature senescence [94]. Arf is anemia [114]. There are increases in DNA mutations, also repressed transcriptionally by early growth re- DNA oxidation, and loss during organism sponse protein 1 (Egr1) and Zbtb7a (pokemon). Egr1- aging. It seems reasonable to assume that all three null MEFs express increased levels of Arf, but escape factors, activation of the p16Ink4a/Arf locus, telomere replicative senescence with reduced expression of p53, shortening, and accumulation of DNA damage, have p21Cip1/Waf1 and other p53 downstream proteins [95]. cooperative effects on aging in physiological situations. Zbtb7a-null MEFs become senescent prematurely Understanding the mechanisms of cellular senescence because of the upregulation of Arf expression, because is currently of wide interest and it is important that we senescence can be overcome by mutation of Arf [96]. identify new components of this process, such as JDP2.

SENESCENCE AND AGING IN HUMANS HISTONE CHAPERONES AND MICE Activation and repression of gene expression at the Cellular senescence appears to be related to organism chromatin level are subject to regulation by enzymes aging. Cellular senescence involves processes that that reorganize and rearrange the chromatin template include telomere shortening, accumulation of DNA [10]. Both ATP-dependent chromatin-remodeling com- damage, and activation of the p16Ink4a/Arf locus. The plexes and histone chaperones mediate an increase in

Kaohsiung J Med Sci October 2010 • Vol 26 • No 10 519 Y.C. Huang, S. Saito, and K.K. Yokoyama the accessibility of promoters to transcription factors, activation of transcription [127]. NAP-1 is, to date, and facilitate histone-exchange reactions within the the best characterized histone-chaperone protein. The nucleosomes [115,116]. Histone-exchange reactions are crystal structure of NAP-1 reveals that it includes a important because they allow histone variants to be long α helix, which is responsible for homodimeriza- incorporated into nucleosomal arrays independently tion, and a four-stranded antiparallel β sheet, as do of the synthesis of DNA. The deposition of histone other histone-chaperone proteins [128]. variants, such as H2A.Z, has a major impact on gene A protein that is involved in the sorting of proteins expression because these variants are known to be to vacuoles, designated Vps75, has been identified as localized within specific transcriptional domains and a member of the NAP-1 family of histone-chaperone within the [117,118]. proteins in yeast [129]. It has a preference for (H3–H4)2 In yeast cells, transcription is accompanied by the tetramers and forms a complex with Rtt109 (a protein disruption of nucleosomal structures, which suggests that participates in the regulation of Ty1 transposition) an inverse correlation between gene activation and [130]. The complex is composed of acetylated-only nucleosome assembly [119]. Although sliding mecha- free histone H3 in vitro, with no detectable activity nisms have been proposed to explain this phenome- towards nucleosomal H3 [131]. Thus we speculate non, experimental evidence suggests that nucleosome that acetylation of lysine 56 of H3 is, at least in part, displacement can occur via disassembly of the nucle- regulated by the inability of Rtt109–Vsp75 HAT com- osome that involves the removal of histones [7–10]. plexes to acetylate nucleosomal H3 during the G2/M Analysis of the expression of an inducible gene for phase of the cell cycle [131]. During DNA replication, -2 also suggests the removal of histones from Rtt109 acetylates lysine 56 of histone H3 to promote the promoter of this mammalian gene upon activation genome stability [132,133] in the premeiotic and mei- of transcription [120]. Histone chaperones are key play- otic S phases, and its activity is detectable when DNA ers in the removal of histones in this context [121]. is damaged [134,135]. Efficient acetylation by Rtt109 For example, nucleosome disassembly is mediated requires a histone-chaperone protein, either ASF1 or by anti-silencing function 1 (ASF1)/CCG-1-interacting Vsp75, but not chromatin-assembly factor-1 (CAF-1) factor (CIA), which is a histone chaperone and is essen- [130]. By contrast, chromatin-assembly factor-1 and tial for activation of gene transcription [121]. During Rtt106p mediate the formation of heterochromatin by gene repression, however, ASF1/CIA-independent contributing to the spreading of Sir protein during the reassembly of nucleosomes is observed in the same early stages of heterochromatin formation [136]. system [121]. Thus regulation of transcription includes English et al [137] have determined the crystal struc- the disassembly of nucleosomes for gene activation, ture of a histone chaperone (ASF1/CIA) that binds to and deposition of histone nucleosomes and assembly a histone H3–H4 heterodimer. ASF1/CIA physically of nucleosomes for establishment of the basal or re- blocks formation of (H3–H4)2 tetramers and the C pressed state. Some histone chaperones function with terminus of H4 undergoes a dramatic conformational components of several chromatin-related complexes, change upon binding to ASF1. Within nucleosomes, the which include HATs [122], HDACs [123], and the C terminus of H4 (residues 93–102) makes contact ATP-dependent chromatin-remodeling complex [124]. with H2A and is bound within the nucleosome [5]. Thus, acting in concert with other chromatin-related During nucleosome disassembly, H2A–H2B dimers factors, histone chaperones play important roles in are removed by other histone chaperones and ATP- nuclear events that involve chromatin templates. dependent remodeling complexes, which exposes the The histone chaperone known as nucleosome- C terminus of H4 in the tetrasome complex [5,137,138]. assembly protein-1 (NAP-1) acts autonomously to ASF1 recognizes and captures the C terminus of exchange H2A–H2B dimers and to incorporate his- H4 in the tetrasome, which is the site of complex tone variants into intact nucleosomes [118,125]. In vitro, changes in the conformation of the H4 C terminus in

NAP-1 has been shown to facilitate the binding of the ASF–(H3–H4)2 complex. ASF1 then dissociates the transcription factors to sites of nucleosomes, and this H3–H4 dimer that is bound to ASF1. Other histone process requires the disassembly of nucleosomes [126]. chaperones and chromatin-remodeling complexes NAP-1 also associates with the co-activator p300/CBP, might also be involved in the dissociation of the with the resultant enhancement of p300-mediated (H3–H4)2 tetramer. The reverse relationship might be a

520 Kaohsiung J Med Sci October 2010 • Vol 26 • No 10 Control of senescence by JDP2 feature of nucleosome assembly. The histone (H3–H4)2 associating with a complex that also has HAT activity tetramer-disrupting activity of ASF1/CIA and the cry- [152]. The crystal structure that demonstrates recogni- stal structure of the ASF1/CIA–histone H3–H4 dimer tion by WDR5 of lysine 4 dimethylated H3 shows how complex provide some insight into the mechanisms the WDR repeats distinguish between the di- and of both the assembly and disassembly of nucleosomes. trimethylated lysine 4 residues of H3 [153,154]. Both Recently Muto et al [139] have reported a compar- so-called tudor domains and WD-domain-containing ison of the crystal structures of template-activating proteins are present in various HAT complexes, includ- factor (TAF)-1β and NAP-1. They have found that the ing SAGA. Recently, a plant homeodomain, the PHD two proteins are folded similarly, with the exception of finger, which has been found in a number of proteins the inserted helix. These backbone helices are shaped in various HAT complexes, has been shown to bind differently, and the relative disposition of each back- to trimethylated lysine 4 of H3 [155–157]. An emerging bone helix and the “earmuff” domains between the theme for these various chromatin-binding domains two proteins differ significantly. The histone-chaperone is that they are often associated with enzymes that activity is associated with the lower surface of the modify or alter chromatin, such as Eaf3 and WDR5 earmuff domains [139]. Akai et al have reported that [157,158], in the case of Gcn5 HAT [149]. To under- the molecular complex between CIA/ASF-1 and the stand fully the functions of these domains, we need double bromodomain complex plays a key role in site- to study their locations within relevant protein specific histone eviction at the active promoter [140]. complexes.

DOMAINS THAT INTERACT WITH INTERACTION OF TRANSCRIPTION FACTORS CHROMATIN WITH HISTONES AND NUCLEOSOMES

We have defined five groups of nucleosome-binding IIIA (TFIIIA) is a 40-kDa protein, domains: bromodomains, chromodomains, WD40 with nine domains, that binds specifically repeats, tudor domains, and PHD fingers. Bromo- to the internal promoter of the gene for 5S RNA and to domains recognize and bind acetylated lysine residues the N-terminal tail domains of histones H3 and H4, [141,142]. For example, general control nonrepressive but not those of H2A and/or H2B, and directly mod- 5 (Gcn5) contains a bromodomain that is important ulates its ability to bind nucleosomal DNA [159,160]. for the binding, recognition and retention of SAGA A new class of HAT-regulatory proteins has been on acetylated promoter nucleosomes [143]. Chromod- identified. These proteins block HAT activity via bind- omains bind methylated lysine tails specifically. The ing to and masking of the histone themselves. This chromodomain of heterochromatin protein 1 binds class includes the subunits of the inhibitor of histone methylated lysine 9 of H3, whereas the chromod- acetyltransferase (INHAT) complex; TAF-1α, TAF-1β, omain of Polycomb binds methylated lysine 27 of H3 and pp32, as well as ataxin 3; silencing or [144–148]. The chromodomain of Eaf3, a protein sub- /nuclear recep- unit shared by the HAT complex NuA4 and the HDAC tor corepressor; and proline-, glutamate- and leucine- complex Rpd3S, is important for the recognition of and rich protein 1 [161–167]. Thanatos-associated protein 7 binding to methylated lysine 36 of H3 [149–151]. Loss is known to associate with TAF-1β and to repress of this binding leads to increased acetylation in tran- transcription by inhibition of histone acetylation scribed regions and the formation of spurious tran- [168,169]. This is a novel co-repressor that activates scripts that are initiated within open reading frames INHAT binds directly to nucleosomes and core his- [151]. Unlike acetylation, methylation can occur once, tones, and prevents acetylation by HATs, thus acting twice or three times, generating mono-, di- and as a bona fide INHAT [170]. PU.1, a member of the Ets trimethylated histones, and the protein domains that family of oncoproteins, inhibits CBP-mediated acety- bind to methylated histones associate differentially lation of GATA-binding protein-1 (GATA-1) and ery- with histones with varying levels of methylation. The throid Krüppel-like factor 2 (EKLF2), as well as of WD-domain-containing protein WDR5 binds dimethy- histones, and disrupts acetylation-dependent tran- lated lysine 4 of H3 preferentially in vitro, in addition to scriptional events [171]. Moreover, PU.1 recruits the

Kaohsiung J Med Sci October 2010 • Vol 26 • No 10 521 Y.C. Huang, S. Saito, and K.K. Yokoyama retinoblastoma tumor-suppressor protein, a histone cells are exposed to UV irradiation, oxidative stress, Suv39H, and heterochromatin pro- or inhibitor-induced depressed levels of translation tein 1 [172]. Similarly, proliferating cell nuclear anti- by JNK [185]. Although a novel JNK-docking domain gen binds to p300 to inhibit its HAT activity in vitro is necessary for the p38-mediated phosphorylation of and to block HAT-dependent transcription in vivo JDP2 at residue 148, this domain is not suf- [173]. TAF-1β and pp32 have also been shown to ficient for this process [186]. JDP2 binds to both cAMP- interact with -α (ER-α), to inhibit the and TRE-response elements on DNA as a homodimer, ERα-mediated activation of transcription, and activa- and as a heterodimer with ATF-2 and members of the tion of ER-α acetylation by p300 [166,167]. Moreover, Jun family, respectively [180,181]. JDP2 inhibits UV- TAF-1β also interacts with the Sp-1 transcription fac- induced apoptosis by suppressing the transcription of tor and with KLF5, negatively regulating binding to the p53 gene [187]. Given the roles of AP-1 in cellular DNA and activation of transcription by these factors transformation and the reported repression of Jun- [174,175]. Transcription factor nuclear factor-κB p50 and ATF-2-mediated transcription by JDP2, we have can accommodate distorted, bent DNA within the demonstrated that JDP2 inhibits the oncogenic trans- nucleosome [176], whereas the DNA-binding domain formation of chicken embryonic fibroblasts [188]. JDP2 of c-Myb binds to the N-terminal tails of H3 and H3.3, also modulates the expression of and p21, and binding of c-Myb facilitates acetylation of histone which have opposing effects on cell-cycle progression. tails [177]. Moreover, kinetochore-null protein 2, which JDP2 interferes with the progression of the cell cycle has a c-Myb-like DNA-binding domain is specifically by reducing the levels of cyclin D1 and at the same required for loading of centromere-specific variants time, increases the expression of p21 [189,190]. The of histone H3 (centromere protein A) in nematodes forced expression of JDP2 promotes the myogenic and mammalian cells [178]. The recruitment of re- differentiation of C2C12 cells, which is accompanied pressive macroH2A nucleosomes requires direct by the formation of C2 myotubes and the strong expres- interactions between ATF-2 bound to the nearby sion of major myogenic markers. Moreover, the ectopic AP-1 site and macroH2A and it is regulated by DNA- expression of JDP2 in cells induces induced protein allostery [179]. Thus the above- incomplete myogenesis and the incomplete forma- mentioned sequence-specific DNA-binding factors tion of myotubes. These cells become committed to might regulate transcription either via histone cores differentiation via the p38-MAPK pathway [190]. A or tails, as well as via the structure of nucleosomes, similar enhancement of cell differentiation has been in conjunction with other proteins that bind to the reported during induction of osteoclast formation by chromatin. the receptor activator of the nuclear factor κB (RANKL) [191]. Unlike other members of the AP-1 family, the levels of JDP2 remain constant in response JDP2 REGULATES AP-1-MEDIATED to a large variety of stimuli, such as UV, irradiation, ACTIVATION OF TRANSCRIPTION and (RA), which affect the levels of other factors involved in cell-cycle control. The induction JDP2 has been identified as a binding partner of c-Jun of JDP2 expression has only been observed during in yeast two-hybrid screening experiments, based on the differentiation of F9 cells to muscle cells and the recruitment of the SOS system [180]. JDP2 forms osteoclasts. Therefore, JDP2 might provide a thresh- heterodimers with c-Jun and represses AP-1-mediated old for exit from the cell cycle and a commitment to activation of transcription [180]. Similarly, JDP2 was differentiation. Further studies on regulation of the isolated by yeast two-hybrid screening with activa- cell cycle and differentiation of cells induced by JDP2 tion transcription factor-2 (ATF-2) as the “bait” [181]. should be instructive. It is also interesting that JDP2 JDP2 has also been shown to associate with the is one of the candidate oncoproteins that collaborate CAAT/enhancer-binding protein-γ [182] and the in the oncogenesis associated with the loss of p27, as a [183]. JDP2 is constitutively result of insertional mutations [192]. Recent studies of expressed in many cell lines and represses the tran- tumor cells have demonstrated that JDP2 is a tumor scriptional activity of AP-1 [184]. Moreover, JDP2 is suppressor [193]. We have also found that JDP2 is a rapidly phosphorylated at threonine residue 148 when repressor of activation of transcription via AP-1, and

522 Kaohsiung J Med Sci October 2010 • Vol 26 • No 10 Control of senescence by JDP2 a negative regulator of RA-induced differentiation of JDP2 HAS INTRINSIC NUCLEOSOME- mouse embryonic F9 cells [194,195]. ASSEMBLY ACTIVITY IN VITRO

The TAF-Iβ protein, which is a component of the JDP2 INHIBITS HAT ACTIVITY INHAT complex identified by Seo et al [162,163], is a histone chaperone that binds directly to core histones We have reported previously that JDP2 represses the and facilitates the assembly of nucleosomes in vitro. transactivation mediated by p300 [195]. Both p300 JDP2 interacts directly with all the core histones tested and ATF-2 have HAT activity [196,197]. It was recently and inhibits the p300-mediated acetylation of those his- shown that p300 acetylates ATF-2 protein in vitro at tones. To our surprise, JDP2 also introduces super- lysine residues 374 and 357 and that ATF-2 is essen- coils into circular DNA in the presence of core histones, tial for the acetylation of histones H4 and H2B in vivo to levels similar to those observed for yeast CCG1- [198,199]. We found that acetylation by p300 is inhibited interacting factor 1 protein (yCia1p) and CIA1. There- in a dose-dependent manner by JDP2, when added fore, JDP2 appears to have significant histone chaperone exogenously. We also found that JDP2 was not acety- activity in vitro [195]. We have also shown that the lated by p300 under our experimental conditions. The HAT-inhibitory activity of JDP2 is involved, to some inhibitory effect of JDP2 on histone acetylation is in- extent, in the repression of transcription by JDP2, duced by p300, CREB binding protein (CBP), p300/CBP whereas the maximal capacity of JDP2 to suppress associated factor (PCAF), and Gcn5. Overexpression the RA-mediated activation of the c-Jun promoter of JDP2 apparently represses RA-induced acetylation (Figure 1) [195; Figure 1] and to suppress adipocyte of lysine residues 8 and 16 of histones H4 and H3. differentiation [200] requires recruitment of HDACs.

X1 = ATF-2, ATF-7, JunD, JunB, JDP2 etc. HDAC3

NCoR/SMART

H4K8 H3K K K KK KK K H4K16 H3K JDP2 X1 K

DRE

K K K K K K K K K K K K K K p300, pCAF, X2 + RA BRG1-based PP SWI/SNF p38 a/b ATPase JDP2, NCoR/SMART, HDAC3

PCAF Ini1/ P IID/Pol II SNF5 p160 p300 TBP P P Ac Ac Ac Ac TAF12 Ac Ac SWI BAF RXRRAR X2 X1 (TAF4) TAFs Ac /SNF 60 RARE DRE TATA c-Jun

Ac Ac AcAc Ac X1 = ATF-2, ATF-7, JunD, JunB etc. Ac X2 = c-jun etc.

Figure 1. Schematic representation of the signal pathways of retinoic acid-induced differentiation of mouse embryonic F9 cells. At the undifferentiated stage of F9 cells, 3, nuclear corepressor, silencing mediator or corepressor and Jun dimerization protein 2 are recruited to the differentiation in the promoter region of the c-jun gene to induce heterochromatin. In response to retinoic acid, the signals of p38, BRG1-based SWI/SNF complex, Ini1/Snf5 complex and p300/PCAF complex are recruited to the differentiation response element of the c-jun promoter, and the c-jun gene is finally activated.

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JDP2 REGULATES REPLICATIVE SENESCENCE the presence of 3% oxygen, which suggests that its expression depends on oxygenic stress, and that accu- We have analyzed the aging-dependent proliferation mulated JDP2 plays a role in the transcriptional acti- of MEFs from Jdp2–/– transgenic mice in the pres- vation of p16Ink4a/Arf. Studies based on chromatin ence of environmental (20%) or low (3%) oxygen. The immunoprecipitation have demonstrated that methy- Jdp2–/– MEFs continued to divide, even after 6 weeks, lation of H3K27 at the p16Ink4a/Arf locus is higher in whereas the wild-type MEFs almost stopped prolifer- Jdp2–/– than wild-type MEFs, and that the binding of ating and entered senescence under environmental PRC1 and PRC2 to the p16Ink4a and Arf promoters is oxygen. Conversely, neither wild-type nor Jdp2–/– more efficient in Jdp2–/– MEFs. These observations MEFs succumbed to replicative senescence at lower suggest that, in the absence of JDP2, H3K27 is methy- oxidative stress. These results demonstrate that MEFs lated by PRC2 and the p16Ink4a/Arf locus is silenced by that lack Jdp2 can escape from the irreversible growth PRC1, whereas the increased expression of JDP2 helps arrest caused by environmental oxygen. The expres- to release PRC1 and PRC2 from the p16Ink4a/Arf locus, sion of p16Ink4a and Arf were repressed in aged Jdp2–/– thereby reducing H3K27 methylation. Our data dem- MEFs (40 days) compared with their levels in wild- onstrate that JDP2 is an important factor for regula- type MEFs. In 3% oxygen, at the equivalent time (40 tion of cellular senescence. The loss of JDP2 allows days), wild-type MEFs expressed lower levels of MEFs to escape senescence and conversely, overex- p16Ink4a and Arf compared with those in 20% oxygen, pression of JDP2 induces cell-cycle arrest. The absence whereas Jdp2–/– MEFs maintained low-level expres- of JDP2 reduces the expression of both p16Ink4a and sion of p16Ink4a and Arf. These observations indicate Arf, which inhibit cell-cycle progression. We propose that the aging-associated expression of p16Ink4a and a model that takes into account these results. The Arf is dependent on oxygen stress and that JDP2 con- accumulation of oxidative stress and/or other envi- trols the expression of both p16Ink4a and Arf. We found ronmental stimuli during aging upregulate JDP2 no dramatic downregulation of the upstream repres- expression in primary untransformed cells. Increased sors of p16Ink4a/Arf, Bmi1 and Ezh2, in the absence of JDP2 helps to remove PRC1 and PRC2, which are JDP2, which suggests that JDP2 does not regulate responsible for the methylation of histone H3, from their expression. JDP2 expression in wild-type MEFs the p16Ink4a/Arf locus, which leads to increased increases in the presence of 20% oxygen, but not in p16Ink4a and Arf expression and entry into senescence

− − Jdp2 /

WT Proliferative Proliferative Low oxygen (3%) WT

− − Jdp2 / − − Jdp2 / High oxygen (20%) Young WT MEF Proliferative Arf

Ink4a Up-regulation

Senescenced

Figure 2. Model for the epigenetic regulation of the p16Ink4a/Arf locus by Jun dimerization protein 2 (JDP2). Young primary cells exposed to oxidative stress accumulate JDP2. In the presence of JDP2, polycomb repressive complexes 1 and 2 dissociate from the p16Ink4a/Arf locus, and histone H3 on the promoter is demethylated. Finally, p16Ink4a and Arf are expressed and the aged cells become senescent.

524 Kaohsiung J Med Sci October 2010 • Vol 26 • No 10 Control of senescence by JDP2

Ink4a/Arf locus of young cells Ink4a/Arf locus of aged cells Stress

PRC1 PRC2

JDP2 Bmi Ezh up-regulation

PRC1 PRC2 Me

Bmi Ezh Histone Histone

Histone Histone Off Histone Histone On

Me Me

Cell growth p16Ink4a expression p19Arf expression Growth arrest Senescence

Figure 3. Proposed model of the epigenetic regulation of the expression of the genes for p16Ink4a and Arf by Jun dimerization protein 2 (JDP2). Exposure of young primary cell cultures to aging stress leads to the accumulation of JDP2. JDP2 binds to histones and inhibits the methylation of H3K27 at the p16Ink4a/Arf locus. As a result, polycomb repressive complexes 1 and 2 fail to form stable repressive complexes and are released from the locus. The consequent expression of p16Ink4a and Arf in the aged cells leads to senescence.

[76; Figure 2]. There is some evidence that Jdp2 irreversible cell-cycle arrest by activating the Rb and acts as a tumor suppressor: Jdp2 inhibits the Ras- p53 pathways, respectively. The expression of p16Ink4a dependent transformation of NIH3T3 cells [193] and and Arf is epigenetically regulated by PRC1 and PRC2, Jdp2 gene disruptions are often found in lymphomas which associate with these loci, methylate histone H3 induced by insertional mutagenesis caused by the in young cells, and dissociate in aged and senescent Moloney murine leukemia virus in MYC/Runx2 cells. Several factors that upregulate or downregu- transgenic mice [201]. Here, we suggest that Jdp2 not late the expression of the p16Ink4a/Arf locus have been only inhibits the transformation of cells, but also reported. It is now important to establish how these plays a role in the induction of cell senescence as well different factors regulate senescence. Do they affect as cell cycle arrest [202]. These functions of JDP2 only euchromatin or do they also regulate hetero- might be important for its role in inhibiting tumor chromatin? Do they modify the chromatin structure formation. Our findings also provide new insights by recruiting HDACs, HATs, histone methyltrans- into the molecular mechanisms by which senescence ferases, histone chaperones, and/or other molecules? is induced in the context of the epigenetic regulation Addressing these precise functions in the context of of the p16Ink4a/Arf locus. epigenesis should help us to understand how senes- cence and, in a broader context, aging, are regulated.

CONCLUDING REMARKS ACKNOWLEDGMENTS Like differentiation and tumorigenesis, senescence is associated with dynamic changes in gene expression, The authors thank Drs K. Itakura, G. Gachelin, which are regulated by . Here, R. Chiu, R. Eckner, P.-T. Yao, T. Kouzarides, C. D. Allis, we have shown that the expression of p16Ink4a and D.M. Livingston and M. Horikoshi for their helpful Arf is upregulated in response to accumulating envi- discussions and reagents. This work was supported ronmental stresses, oncogenic signaling, and DNA- by the BioResource Center of RIKEN (to K.K.Y) and damaging signals, and that they in turn induce a grant from Taiwan KMU (KMU-EM-99-3 to K.K.Y.).

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