Gene name - kismet
Cytological map position - 21B4--5
Function - enzyme, chromatin constituent
Keywords - regulation of Pol II transcription, trithorax family
Symbol - kis
FlyBase ID: FBgn0266557
Genetic map position - 2L
Classification - SNF2-related, chromodomains, ATP dependent helicase, C-terminal BRK domain
Cellular location - nuclear
|Recent literature||Gervais, L., van den Beek, M., Josserand, M., Salle, J., Stefanutti, M., Perdigoto, C. N., Skorski, P., Mazouni, K., Marshall, O. J., Brand, A. H., Schweisguth, F. and Bardin, A. J. (2019). Stem cell proliferation is kept in check by the chromatin regulators Kismet/CHD7/CHD8 and Trr/MLL3/4. Dev Cell 49(4): 556-573.e556. PubMed ID: 31112698
Chromatin remodeling accompanies differentiation, however, its role in self-renewal is less well understood. This paper reports that in Drosophila, the chromatin remodeler Kismet/CHD7/CHD8 limits intestinal stem cell (ISC) number and proliferation without affecting differentiation. Stem-cell-specific whole-genome profiling of Kismet revealed its enrichment at transcriptionally active regions bound by RNA polymerase II and Brahma, its recruitment to the transcription start site of activated genes and developmental enhancers and its depletion from regions bound by Polycomb, Histone H1, and heterochromatin Protein 1. The Trithorax-related/MLL3/4 chromatin modifier regulates ISC proliferation, colocalizes extensively with Kismet throughout the ISC genome, and co-regulates genes in ISCs, including Cbl, a negative regulator of Epidermal Growth Factor Receptor (EGFR). Loss of kismet or trr leads to elevated levels of EGFR protein and signaling, thereby promoting ISC self-renewal. It is proposed that Kismet with Trr establishes a chromatin state that limits EGFR proliferative signaling, preventing tumor-like stem cell overgrowths.
|Latcheva, N. K., Viveiros, J. M. and Marenda, D. R. (2019). The Drosophila chromodomain protein Kismet activates steroid hormone receptor transcription to govern axon pruning and memory in vivo. iScience 16: 79-93. PubMed ID: 31153043
Axon pruning is critical for sculpting precise neural circuits. Although axon pruning has been described in the literature for decades, relatively little is known about the molecular and cellular mechanisms that govern axon pruning in vivo. This study shows that the epigenetic reader Kismet (Kis) is required for developmental axon pruning in Drosophila mushroom bodies. Kis binds to cis-regulatory elements of the steroid hormone receptor Ecdysone receptor (Ecr) gene and is necessary for activating expression of EcR-B1. Kis promotes the active H3K36 di- and tri-methylation and H4K16 acetylation histone marks at the Ecr locus. Transgenic EcR-B1 can rescue axon pruning and memory defects associated with loss of Kis, and the histone deacetylase inhibitor SAHA also rescues these phenotypes. EcR protein abundance is the cell-autonomous, rate-limiting step required to initiate axon pruning in Drosophila, and the data suggest this step is under the epigenetic control of Kis.
The Drosophila trithorax group gene kismet (kis) was identified in a screen for extragenic suppressors of Polycomb (Pc) and subsequently shown to play important roles in both segmentation and the determination of body segment identities. One of the two major proteins encoded by kis (Kis-L) is related to members of the SWI2/SNF2 and CHD families of ATP-dependent chromatin-remodeling factors. To clarify the role of Kis-L in gene expression, its distribution on larval salivary gland polytene chromosomes was examined. Kis-L is associated with virtually all sites of transcriptionally active chromatin in a pattern that largely overlaps that of RNA Polymerase II (Pol II). The levels of elongating Pol II and the elongation factors SPT6 and CHD1 are dramatically reduced on polytene chromosomes from kis mutant larvae. By contrast, the loss of Kis-L function does not affect the binding of PC to chromatin or the recruitment of Pol II to promoters. These data suggest that Kis-L facilitates an early step in transcriptional elongation by Pol II (Srinivasan, 2005).
The homeotic (Hox) genes of the Antennapedia and bithorax complexes encode homeodomain transcription factors that specify the identities of body segments by regulating the transcription of downstream target genes. The transcription of Hox genes must be regulated precisely, because their inappropriate expression leads to dramatic alterations in segmental identities. In Drosophila, the initial patterns of Hox transcription are established early in embryogenesis by transcription factors encoded by segmentation genes. During subsequent development, these patterns are maintained by two ubiquitously expressed groups of regulatory proteins: the Polycomb group (PcG) of repressors and the trithorax group (trxG) of activators. Counterparts of Drosophila PcG and trxG genes play conserved roles in other metazoans, including humans. Although the molecular mechanisms used to maintain heritable states of Hox transcription remain relatively mysterious, a growing body of evidence suggests that they involve changes in chromatin structure. PcG proteins silence the transcription of their target genes via cis-regulatory elements known as Polycomb-response elements (PREs). Two complexes of Drosophila PcG proteins have been identified: PRC1 (which contains PC and other PcG proteins) and the ESC/E(Z) complex. The ESC/E(Z) complex methylates lysine 27 of histone H3; this modification is required for PcG silencing in vivo and may help recruit PRC1 or stabilize the binding of PRC1 to PREs (Srinivasan, 2005 and references therein).
How does PRC1 silence transcription once targeted to a PRE? One popular model is that PRC1 packages chromatin into a configuration that is inaccessible to transcription factors or the general transcription machinery. However, recent studies have indicated that PRC1 may repress transcription via more selective mechanisms. For example, PRC1 may block transcription via direct interactions with components of the basal transcription machinery, as evidenced by the presence of TFIID subunits in PRC1. Furthermore, DNA-binding activators TBP and Pol II are present at promoters repressed by PRC1, suggesting that PRC1 selectively interferes with events downstream of Pol II recruitment (Srinivasan, 2005 and references therein).
Other potential targets of PRC1 include the members of the trxG of activators. Mutations in many trxG genes suppress Pc mutations and cause homeotic transformations because of the failure to maintain active states of Hox transcription. The majority of trxG proteins characterized to date have been implicated in either chromatin remodeling or the covalent modification of nucleosomal histones. For example, the trxG genes trithorax (trx) and absent, small or homeotic 1 (ash1) encode SET domain proteins with histone methyltransferase activity; these histone-modifying enzymes counteract silencing by PcG proteins in vivo. Another trxG gene, brahma (brm), encodes a member of the SWI2/SNF2 family of ATPases. The Brm ATPase, together with the trxG proteins Moira (Mor) and Osa, are subunits of a 2 MDa chromatin-remodeling complex that is highly related to the yeast SWI/SNF and RSC, and the human BAF and PBAF complexes. By altering the structure or positioning of nucleosomes, these complexes facilitate the binding of transcription factors and other regulatory proteins to chromatin. The BRM complex plays a global role in transcription by Pol II and is therefore an excellent candidate for a target of PRC1 repression. Consistent with this possibility, PRC1 strongly inhibits chromatin remodeling by human SWI/SNF in vitro (Srinivasan, 2005 and references therein).
Like brm, mor and osa, the trxG gene kismet (kis) was identified in a screen for extragenic suppressors of Pc, suggesting that it acts antagonistically to Pc to activate homeotic gene expression. Loss of maternal kis function causes segmentation defects identical to those caused by mutations in the pair-rule gene even-skipped (eve) (Daubresse, 1999). Loss of zygotic kis function causes homeotic transformations, including the transformation of first leg to second leg and the fifth abdominal segment to a more anterior identity (Daubresse, 1999). These phenotypes are identical to those resulting from the decreased transcription of the Hox genes Sex combs reduced (Scr) and Abdominal-B (Abd-B). Thus, kis plays a dual role during development; maternal kis activity is required for embryonic segmentation and zygotic kis activity is required for the control of cell fate. Mutations in kis have also been recovered in screens for genes involved in the Notch and Ras signaling pathways, suggesting that its function is not limited to segmentation and the determination of body segment identities (Go, 1998; Therrien, 2000; Verheyen, 1996, Srinivasan, 2005 and references therein).
Pc mutants are exquisitely sensitive to changes in kis levels; kis mutations and deficiencies strongly suppress homeotic phenotypes resulting from Hox derepression in Pc heterozygotes, while kis duplications enhance them (Daubresse, 1999; Kennison, 1988). This strong, dose-dependent interaction suggests that the functions of kis and Pc are intimately related. A functional antagonism between kis and Pc could occur at several levels. For example, Kis-L may directly counteract the binding of PRC1 or the ESC/E(Z) complex to chromatin by altering the structure or positioning of nucleosomes at PREs. Alternatively, Kis-L might play a more global role in transcription by Pol II, as has been observed for the BRM complex. In this case, PRC1 might silence the transcription of Hox genes by blocking chromatin remodeling by Kis-L (Srinivasan, 2005).
To clarify the mechanism of action of kis, the distribution of Kis-L and other proteins involved in chromatin remodeling and transcription was compared on salivary gland polytene chromosomes. Kis-L, like Brm, is associated with virtually all transcriptionally active regions of the Drosophila genome. The levels of elongating Pol II and the elongation factors SPT6 and CHD1 are dramatically reduced on polytene chromosomes from kis mutant larvae. By contrast, the loss of Kis-L function does not affect the binding of PC to chromatin or the recruitment of Pol II to promoters. These findings suggest that Kis-L facilitates an early step in transcriptional elongation by Pol II (Srinivasan, 2005).
Eukaryotic transcription involves a highly coordinated cycle of events, including the assembly of the pre-initiation complex, initiation, promoter clearance, elongation and termination. In theory, any step in the transcription cycle could be subject to developmental regulation by PcG and trxG proteins. Basal transcription factors and Pol II are recruited to the promoter during the initial stages of transcription. After Pol II is recruited to a promoter, the phosphorylation of the C-terminal domain (CTD) of its largest subunit coincides with promoter clearance and the transition from initiation to the elongation phase of transcription (Svejstrup, 2004). A number of CTD kinases have been identified, including CDK7 (a subunit of TFIIH) and CDK9 (a component of P-TEFb), which phosphorylate, respectively, serine 5 and serine 2 residues of the CTD. The phosphorylation of serine 5 is highest near the promoter, whereas the phosphorylation of serine 2 increases as Pol II proceeds toward the 3' end of genes (Cho, 2001; Komarnitsky, 2000). CTD phosphorylation modulates interactions between Pol II and other factors involved in transcription. For example, phosphorylation of the CTD may disrupt interactions between Pol II and mediator, thus facilitating promoter clearance (Pokholok, 2002; Svejstrup, 1997). The phosphorylated CTD can also act as a docking site for factors involved in mRNA processing and termination (Hirose, 2000; Proudfoot, 2002) (Srinivasan, 2005).
The current findings strongly suggest that Kis-L plays a global role in transcription by Pol II. Consistent with this view, Kis-L is associated with virtually all transcriptionally active regions of chromatin in salivary gland nuclei. The initial stages of transcription are normal in kis mutant larvae; Pol II is efficiently recruited to promoters and the phosphorylation of serine 5 of the CTD is not affected. However, the absence of Pol IIoser2 and the elongation factors SPT6 and CHD1 on the polytene chromosomes of kis mutant larvae strongly suggests that Kis-L is required for an early step in transcriptional elongation (Srinivasan, 2005).
The discovery that Kis-L plays a global role in transcription by Pol II was unanticipated, since previous genetic studies have suggested that kis plays relatively specialized roles in development (Daubresse, 1999). The limited phenotypes resulting from the loss of zygotic kis function may be due to the high maternal contribution of kis gene products. It is also possible that the mutations used in previous genetic studies of kis are not null alleles, or that other factors can partially compensate for the loss of kis function in tissues other than the salivary gland (Srinivasan, 2005).
How might Kis-L facilitate an early step in transcriptional elongation by Pol II? Based on its similarity to chromatin-remodeling factors, it is likely that Kis-L promotes transcription by altering chromatin structure. Nucleosomes and other components of chromatin can repress transcription at many different levels. For example, nucleosomes can interfere with the assembly of the preinitiation complex by blocking access of gene-specific and general transcription factors to promoter regions. Nucleosomes also present a physical barrier to Pol II during transcriptional elongation. Histone-modifying enzymes, chromatin-remodeling factors and numerous other factors are therefore crucial for transcriptional initiation and elongation in a chromatin environment (Srinivasan, 2005).
Recent studies of the mammalian hsp70 gene have suggested that the remodeling of nucleosomes near promoters is important for early stages of transcriptional elongation. Prior to induction, a paused polymerase is located just downstream of the hsp70 promoter. Following induction, heat shock factor 1 targets mammalian SWI/SNF to the hsp70 promoter resulting in the disruption of this nucleosome, thus allowing elongation to proceed. By analogy, Kis-L may promote elongation by remodeling nucleosomes immediately downstream of promoters (Srinivasan, 2005 and references therein).
The presence of two chromodomains in Kis-L suggests that the methylation of N-terminal histone tails may also be important for its targeting or function. This possibility is intriguing in light of recent studies suggesting that histone methyltransferases modulate distinct stages of transcriptional elongation by Pol II. The phosphorylation of serine 5 of the CTD promotes interactions between Pol II and the SET1 methyltransferase, resulting in the methylation of lysine 4 of histone H3 in the vicinity of promoters. The subsequent phosphorylation of serine 2 of the CTD promotes interactions with the SET2 methyltransferase, resulting in the methylation of lysine 36 of histone H3 in the body of transcribed genes. The pattern of histone methylation resulting from the dynamic interactions between Pol II and histone methyltransferases may facilitate the transition from early to late stages of elongation by regulating interactions between chromatin-remodeling factors and nucleosomes near promoters (Srinivasan, 2005 and references therein).
The yeast SET1 histone methyltransferase is a subunit of a large protein complex known as COMPASS. Functional counterparts of yeast COMPASS have been identified in humans; these complexes contain subunits related to Drosophila TRX (human MLL1 and MLL2) and ASH2 (human ASH2L). Human MLL1 and MLL2 methylate lysine 4 of histone H3, as does Drosophila TRX (Smith, 2004), suggesting that they are functional counterparts of SET1. Another Drosophila trxG protein, ASH1, also methylates lysine 4 of histone H3 both in vitro and in vivo (Srinivasan, 2005).
The above findings suggest a plausible model for how Kis-L interacts with other trxG proteins to activate transcription. Perhaps Kis-L, like SWI/SNF and other chromatin-remodeling factors, is targeted to promoters via interactions with transcriptional activators or components of the general transcription machinery. Once targeted to the vicinity of a promoter, Kis-L may recognize promoter-proximal nucleosomes methylated on lysine 4 of histone H3 (by TRX or ASH1) via its chromodomains, leading to the localized remodeling of nucleosomes that pose a barrier to elongation by Pol II (Srinivasan, 2005).
The findings of this study may help explain the functional antagonism between kis and PcG proteins. PcG proteins do not merely render chromatin inaccessible to the general transcription machinery; transcriptional activators, basal transcription factors (including TFIID and TFIIF) and even Pol II are associated with targets of PcG repression. Thus, PcG proteins may act directly on components of the general transcription machinery assembled at promoters. Consistent with this possibility, Pol II is efficiently recruited to an hsp26 promoter silenced by the bxd PRE, but is unable to melt the promoter and initiate transcription (Dellino, 2004). A separate study of a promoter silenced by PcG proteins in its natural context (the Ubx promoter in wing imaginal discs) has revealed that PcG proteins bind to both PREs and a very narrow region just downstream of the start of transcription (Wang, 2004). Although their precise mechanism of action remains to be determined, the above studies suggest that PcG proteins exert their influence during the later stages of transcriptional initiation or early stages of elongation. It is therefore tempting to speculate that PcG proteins may repress transcription by blocking Kis-L activity. Further analysis of the role of Kis-L in transcription, together with the development of systems for analyzing its function in vitro, will be necessary to test this hypothesis and clarify the role of Kis-L in gene expression and development (Srinivasan, 2005).
Members of the Polycomb group of repressors and trithorax group of activators maintain heritable states of transcription by modifying nucleosomal histones or remodeling chromatin. Although tremendous progress has been made toward defining the biochemical activities of Polycomb and trithorax group proteins, much remains to be learned about how they interact with each other and the general transcription machinery to maintain on or off states of gene expression. The trithorax group protein Kismet (KIS) is related to the SWI/SNF and CHD families of chromatin remodeling factors. KIS promotes transcription elongation, facilitates the binding of the trithorax group histone methyltransferases ASH1 and TRX to active genes, and counteracts repressive methylation of histone H3 on lysine 27 (H3K27) by Polycomb group proteins. This study sought to clarify the mechanism of action of KIS and how it interacts with ASH1 to antagonize H3K27 methylation in Drosophila. Evidence is presented that KIS promotes transcription elongation and counteracts Polycomb group repression via distinct mechanisms. A chemical inhibitor of transcription elongation, DRB, had no effect on ASH1 recruitment or H3K27 methylation. Conversely, loss of ASH1 function had no effect on transcription elongation. Mutations in kis cause a global reduction in the di- and tri-methylation of histone H3 on lysine 36 (H3K36) - modifications that antagonize H3K27 methylation in vitro. Furthermore, loss of ASH1 significantly decreases H3K36 dimethylation, providing further evidence that ASH1 is an H3K36 dimethylase in vivo. These and other findings suggest that KIS antagonizes Polycomb group repression by facilitating ASH1-dependent H3K36 dimethylation (Dorighi, 2013).
Since KIS promotes transcription elongation, promotes ASH1 binding and counteracts Polycomb repression, it is suspected that these activities might be functionally interdependent. However, the loss of ASH1 function leads to an increase in repressive H3K27 trimethylation without affecting transcription elongation. Furthermore, the treatment of salivary glands with the elongation inhibitor DRB did not affect the level of ASH1 or H3K27me3 associated with polytene chromosomes. It is therefore concluded that KIS promotes transcription elongation and antagonizes Polycomb repression via distinct mechanisms (Dorighi, 2013).
These findings suggest that the major mechanism by which KIS antagonizes Polycomb group repression is by promoting the association of the trithorax group histone methyltransferases ASH1 and TRX with chromatin. Recent biochemical studies have suggested several mechanisms by which ASH1 and TRX counteract Polycomb repression. A histone modification catalyzed by TRX in vitro (H3K4 trimethylation) disrupts interactions between PRC2 and its nucleosome substrate. H3K4me3 directly interferes with the binding of the PRC2 subunit NURF55 (CAF1) to nucleosomes and inhibits the catalytic activity of E(Z) allosterically through interactions with the SU(Z)12 subunit of PRC2. The relevance of this modification to TRX function in vivo is not clear, however, as the bulk of H3K4 trimethylation in Drosophila is catalyzed by the histone methyltransferase SET1. Another mechanism by which TRX counteracts Polycomb repression was suggested by its physical association with the histone acetyltransferase CBP in the TAC1 complex. The acetylation of H3K27 by CBP directly blocks the methylation of this residue by PRC2. It is therefore tempting to speculate that the diminished binding of TAC1 to active genes contributes to the increased methylation of H3K27me3 observed in kis mutants (Dorighi, 2013).
Other histone modifications, including both the di- and tri- methylation of H3K36, also block the catalytic activity of PRC2 in vitro. In Drosophila, H3K36 trimethylation is catalyzed by SET2, which associates with the elongating RNA Pol II via its phosphorylated CTD. In this way, H3K36me3 becomes concentrated at the 3' ends of genes where it plays a role in preventing cryptic initiation. Consistent with its role in transcription elongation, kis mutations decreased the level of H3K36me3 on polytene chromosomes. Interestingly, H3K36me3 blocks the methylation of H3K27 at genes expressed in the C. elegans germline. Thus, H3K36 trimethylation might represent a conserved mechanism for antagonizing PRC2 function to maintain appropriate patterns and steady-state levels of transcription. Transcription- dependent H3K36 trimethylation is unlikely to be the sole mechanism by which KIS counteracts Polycomb repression, however, because blocking transcription elongation with DRB did not increase the level of H3K27me3 on polytene chromosomes. Furthermore, ash1 mutants display elevated levels of H3K27 methylation without a reduction in H3K36 trimethylation or transcription elongation, suggesting that additional mechanisms exist to counteract repressive H3K27 methylation (Dorighi, 2013).
An antagonism between H3K36 dimethylation and H3K27 trimethylation was suggested by the recent discovery that H3K36me2 inhibits PRC2 function in vitro. This finding, together with recent evidence that ASH1 dimethylates H3K36 in vitro, prompted an investigation of whether ASH1 also dimethylates H3K36 in vivo. The chromosomal distributions of ASH1 and H3K36me2 overlap significantly, consistent with their localization at the 5' end of active genes. Furthermore, the levels of H3K36me2 on the polytene chromosomes of both ash1 and kis mutant larvae were significantly reduced, consistent with the role of KIS in promoting ASH1 binding. Taken together, these observations strongly suggest that KIS antagonizes Polycomb repression by promoting the ASH1-dependent dimethylation of H3K36 (Dorighi, 2013).
The differences in the chromosomal distributions of ASH1 and H3K36me2 and the residual H3K36me2 observed in ash1 mutants are probably due to the presence of another H3K36 dimethylase (MES-4) in Drosophila. In addition to dimethylating H3K36, MES-4 is required for SET2-dependent H3K36 trimethylation in vivo, as revealed by RNAi knockdown of MES-4 both in larvae and in cultured cells. By contrast, this study failed to observe a significant reduction in H3K36me3 levels in ash1 mutant larvae. The findings suggest that ASH1 and MES-4 play non-redundant roles in H3K36 methylation in vivo (Dorighi, 2013).
It is becoming increasingly clear that multiple mechanisms (including the trimethylation of H3K4, the di- and tri-methylation of H3K36 and the acetylation of H3K27) antagonize repressive H3K27 methylation catalyzed by Polycomb group proteins. The current findings suggest that KIS plays a central role in coordinating these activities. By facilitating the binding of TRX and ASH1, KIS promotes H3K27 acetylation and H3K36 dimethylation in the vicinity of active promoters. By stimulating elongation, KIS promotes H3K36 trimethylation over the body of transcribed genes. Thus, KIS appears to counteract Polycomb group repression by promoting multiple histone modifications that inhibit H3K27 methylation by the E(Z) subunit of PRC2 (Dorighi, 2013).
Haploinsufficiency for CHD7, a KIS homolog in humans, is the major cause of CHARGE syndrome, a serious developmental disorder affecting ~1 in 10,000 live births (Janssen, 2012). Infants born with CHARGE syndrome often have severe health complications due to defects in the development of tissues derived from the neural crest, including coloboma of the eye, cranial nerve abnormalities, ear defects and hearing loss, congenital heart defects, genital abnormalities and narrowing or blockage of the nasal passages. Based on the phenotypes associated with kis mutations in Drosophila, it seems likely that some of these defects may stem from changes in gene expression resulting from loss of transcription elongation and inappropriate gene silencing by Polycomb group proteins. The current findings suggest that changes in histone H3 modifications resulting from the loss of CHD7 function might contribute to the broad spectrum of developmental defects associated with CHARGE syndrome (Dorighi, 2013).
kis encodes two major nuclear proteins with molecular weights of 574 kDa (Kis-L) and 225 kDa (Kis-S) (Daubresse, 1999; Therrien, 2000). Kis-L contains an ATPase domain that is highly related to those found in chromatin-remodeling factors, suggesting that Kis-L, like BRM, catalyzes ATP-dependent alterations in chromatin structure. Kis-L also contains two chromodomains and a BRK domain. Chromodomains mediate protein-protein or protein-RNA interactions, and are found in members of the CHD subfamily of ATPases (including Mi-2 and CHD1) and other proteins that interact with chromatin. Some chromodomains are involved in the selective recognition of methylated histone tails. The BRK domain is a 41 amino acid segment of unknown function that is conserved in BRM and its human homologs BRG1 and HBRM (Daubresse, 1999). The Kis-L protein lacks PHD fingers, a domain characteristic of CHD ATPases, and a bromodomain, a domain conserved in SWI2/SNF2 ATPases that mediates interactions with acetylated histone tails. Thus, Kis-L is unusual in that it has characteristics of both the CHD and SWI2/SNF2 subfamilies of ATPases, but is a clear member of neither class. Potential orthologs of kis are present in nematodes, mice and humans, but not yeast, suggesting that it may play a specialized role in transcription or development in higher eukaryotes (Daubresse, 1999; Schuster, 2002; Therrien, 2000; Srinivasan, 2005 and references therein).
kis encodes two major protein isoforms Kis-S and Kis-L which share a common 2105 amino acid C-terminal segment. This common segment contains a BRK domain related to those found in Drosophila Brm and its human orthologs. The long N-terminal segment unique to Kis-L contains an ATPase domain and two chromodomains. By contrast, Kis-S lacks these domains and is therefore unlikely to have chromatin-remodeling activity. The absence of an ATPase domain in Kis-S suggests that it may function as a naturally occurring dominant-negative form of the Kis protein (Srinivasan, 2005).
date revised: 1 May 2005
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