* Department of Biochemistry and Molecular Biology, Health Science Complex, The University of Calgary, Calgary, Alberta, Canada; and Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Colombia, Canada
Correspondence: E-mail: karl{at}ucalgary.ca.
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Abstract |
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Key Words: ING1 PHD finger molecular evolution protein phylogeny
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Introduction |
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The human ING1 gene has three exons that can be alternatively spliced onto a common 3' exon, thereby generating p27ING1d, p33ING1b, and p47ING1a. In addition, internal initiation at an ATG within the common exon generates p24ING1c (Garkavtsev et al. 1999; Jager et al. 1999; Gunduz et al. 2000; Saito et al. 2000). By screening a breast cancer cell cDNA library using ING1 as probe, followed by 5' RACE using normal fetus cDNA, Jager et al. (1999) cloned an ING1 homolog gene, which maps to the X chromosome. The deduced 42amino acid peptide has a calculated molecular mass of 5.0 kDa and shares 76% identity over its length with the much longer ING1 protein. Expression of this gene was detected in all normal tissues tested and in some cancer cell lines using RT-PCR. To date, four additional genes have been identified in humans that encode ING2 to ING5 (Nagashima et al. 2001, 2003; Shiseki et al. 2003). Study of amphibian ING2 genes provides evidence of differential regulation of presumed splice variants of this gene (Wagner et al. 2001). Three forms of ING2 have been cloned in Xenopus laevis; however, whether they are actually splicing isoforms remains to be confirmed.
All ING genes share strongest homology in a region encoding a plant homeodomain (PHD) motif that has been implicated in the regulation of ubiquitination (Coscoy and Ganem 2003), although this function remains controversial (Aravind, Iyer, Koonin 2003; Scheel and Hofmann 2003). More recently, ING PHDs have been identified as binding targets of rare phosphatidylinositol phosphates (PtdInsPs) that function in DNA damageinitiated stress signaling (Gozani et al. 2003). ING1 also translocates to the nucleolus after UV-induced DNA damage (Scott et al. 2001b). This property of UV-induced relocation to nucleoli is shared with several other proteins that may play roles in DNA repair and/or apoptosis, such as nucleolin (Mi et al. 2003), the Werner's syndrome helicase (Leung and Lamond 2003), the CK2 kinase that phosphorylates DNA ligase and topoisomerase 2 (Gerber et al. 2000), hRad17 (Chang et al. 1999), and p53/MDM2/ARF, among others (Klibanov, O'Hagan, and Ljungman 2001; Leung and Lamond 2003; Sugimoto et al. 2003). Mutational studies identified two intrinsic nucleolar translocation sequences (NTS) within the nuclear localization signal (NLS) found in all ING family members (Scott et al. 2001b). p33ING1b also binds to the proliferating cell nuclear antigen (PCNA) through a specific sequence called the PCNA-interacting protein (PIP) domain (Warbrick 1998), which is found in proteins involved in growth inhibition (e.g., p21WAF1), growth arrest after DNA damage (e.g., GADD45), and DNA replication and repair (e.g., FEN1) (Feng, Hara, and Riabowol 2002). The ability of ING proteins to bind to and alter the activity of histone acetyltransferases (HATs), histone deacetylases (HDACs), and factor acetyltransferases (FATs) has also been shown (Loewith et al. 2000; Skowyra et al. 2001; Nagashima et al. 2001; Vieyra et al. 2002; Kuzmichev et al. 2002) (reviewed in Feng, Hara, and Riabowol [2002]).
ING sequences have been reported in human, mouse, rat, frog, fission and budding yeast, Drosophila, and C. elegans, as well as in other species; however, most of these homologs remain unrecognized and uncharacterized in databases, including those of the NCBI. Despite the increasing number of ING homologs that have been identified in different organisms, a comprehensive analysis of the evolution of this protein family has not yet been conducted. No studies have reported on the phylogenetic relationships and evolutionary history of the ING family. Because of their potentially important roles in many central biological processes, a better understanding of the multiple ING family members is of particular research interest, and a comprehensive analysis of the ING family across taxonomically diverse organisms would be useful for future studies.
Evolutionary studies of a protein family can be instrumental in determining structurally conserved regions, leading to useful predictions of protein function (Eisen 1998). Moreover, an examination of the evolutionary history of the protein family may indicate the presence of novel family members. In this study, we have undertaken a comprehensive analysis of publicly accessible databases and selected unpublished sequences to identify as many members of the ING family as possible, to further characterize ING-specific motifs and to present an analysis of the evolutionary relationship among candidate ING members from various species.
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Materials and Methods |
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Multiple Sequence Alignments
All amino acid alignments were performed using the program T_COFFEE (Notredame, Higgins, and Heringa 2000) with default settings. The alignments were then adjusted and shaded using the multiple sequence alignment editor GENEDOC (Nicholas, Nicholas, and Deerfield 1997).
Phylogenetic Analysis
We used PHYLIP version 3.6a3 (Felsenstein 1989) for our phylogenetic analysis. Both distance and parsimony analyses using the protein alignment as input were performed. Bootstrap values were obtained using SEQBOOT and creating 1,000 delete-half Jackknife data sets. The distance analysis was performed by using PROTDIST and subsequently NEIGHBOR with standard parameters, and the parsimony analysis was performed using PROTPARS with standard parameters. In both cases, the "M" option for the analysis of the multiple data sets created with SEQBOOT was invoked.
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Results |
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Protein Sequence Alignments
A database consisting of sequences judged to be members of the ING protein family was compiled (table 1). The ING sequences were a collection from a variety of species, including human, mouse, rat, frogs, fish, mosquito, fruit fly, worms, fungi, and plants. A total of 60 ING/ING-related sequences were included in our study based on their sequence similarity. Multiple sequence alignment of the collected ING sequences has identified four major conserved regions of the ING proteins (fig. 3). Region I consists of conserved leucine/isoleucine amino acid residues. The known leucine zipper of ING2_Hs falls in this conserved region. Region II contains several highly conserved amino acids such as a KIQI/KVQL motif, with well-conserved residues occurring every seven amino acids, suggesting a conserved function on a distinct face of an -helix. The most highly conserved region of ING proteins, the PHD, falls into what we have defined as region III. Although several gaps were introduced in the alignment because of small variations in amino acid sequences, the overall C4-H-C3 zinc-finger motif of the PHD remained intact in the ING proteins across species, from human to plants. The C-terminal region of the ING protein contains the fourth conserved region that is significantly longer in ING1 and ING2 compared with the other ING members. This region contains a PIM. Interestingly, the nuclear localization sequences (NLS) and the nucleolar targeting signals (NTS), although well conserved in vertebrate ING genes (figure 2 and Wagner et al. [2001]), showed a very low degree of conservation within invertebrate and plant species (data not shown), suggesting that ING proteins may be targeted differently.
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Discussion |
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Although the human ING proteins have been intensively studied since the first isoform was cloned (Garkavtsev et al. 1996), studies have been focused primarily on ING1, especially p33ING1b. Although attention has been increasingly brought to bear on other ING members to determine their biological functions, these studies are, necessarily, rather independent and narrowly focused. A systematic examination of the ING proteins from a phylogenomic perspective is beneficial for elucidating protein structure and potential common functions. Multiple amino acid sequence alignment of human ING proteins revealed a considerable number of conserved regions (fig. 2). Many conserved motifs have been shown to be essential for ING functions and activities. For example, the PHD is responsible for binding of phosphatidylinositol phosphates (PtdInsPs) in response to DNA damageinitiated stress signaling (Gozani et al. 2003); the NLS/NTS targets ING1 and, likely, other INGs to different chromatin domains in the nucleus and nucleolus in response to UV-induced DNA damage (Scott et al. 2001b), and the PIP domain targets only the p33ING1b of ING1 to PCNA after DNA damage (Scott et al. 2001a). An additional putative role for PHD fingers has been recently proposed (Ragvin et al. 2004), in which the PHD fingers may serve as signal transducers in the interaction of proteins or protein complexes with nucleosomes. Upon cooperatively interacting with other proteins or protein complexes, the PHD finger is bound to a nucleosome. This model is consistent with previous observations that needle microinjection of expression constructs encoding p33ING1b and p47ING1a resulted in increased or decreased histone H3 and H4 acetylation levels, respectively (Vieyra et al. 2002), and the known involvement of ING proteins in chromatin remodeling and HAT/HDAC interactions (reviewed in Feng, Hara, and Riabowol [2002]).
This bioinformatics/phylogenetic analysis builds upon the initial study presented in Feng, Hara, and Riabowol (2002) and identifies additional structural motifs that might be important for ING function and activity. The PIM found at the C-terminal end of ING1 and ING2 has been recently identified and found to stabilize proteins with particular posttranslational modification (Feng et al. 2004). In addition, interaction of ING with other proteins may be mediated through the candidate phosphorylation-dependent interacting motif (PDIM), which is relatively similar to the canonical RSXpSXP 14-3-3 binding motif. This implies that phosphorylation of this region could recruit proteins important in the modulation of such cellular processes as apoptosis, signal transduction, and cell cycle regulation (reviewed in Hermeking [2003]). We also postulate the existence of an LZL motif near the N-terminus of ING3 to ING5 based on the observation that conserved leucine residues were widely distributed on these sequences similar to the known leucine zipper on ING2. If so, ING3 to ING5 may form homodimers and heterodimers or interact with other leucine zippercontaining proteins, such as transcription factors. Initial results suggest that this is the case, making targeting of particular HAT and HDAC complexes to chromatin considerably more dynamic (Gong et al., personal communication). The partial NTS found on ING3 to ING5 suggests that the ability of these ING proteins to be targeted to the nucleus or to the nucleolus in response to UV-induced DNA damage may be compromised or missing in these isoforms. It is also possible that this might represent a lower affinity motif that could allow a greater degree of partitioning of ING proteins to the cytoplasm. Ongoing experiments are testing these hypotheses.
In our comparative sequence analysis across different species, the four conserved regions of ING proteins was a good indicator of structural/functional conservation. The conserved LZL region (fig. 3, region I) re-emphasizes the potential ability of ING proteins to bind other leucine zippercontaining proteins. It is also very important to emphasize the highly conserved region that has a distinct KIQI/KVQL motif (figs. 2A and 3, region II). Kawaji et al. (2002) independently identified this novel and conserved motif, which they labeled MDS00105 and noted is specific for the mammalian ING family. That analysis subdivided it into three submotifs, Q-E-L-G-D-E-K-[IM]-Q, K-E-[FY]-[SG]-D-D-K-V-Q, and [LM]-E-D-A-D-E-K-V-[AQ], that were relatively specific for ING1/ING1L, ING1-homolog, and ING3 subfamilies, respectively. Our results shown in figure 3 extend their observations in that the ING1/ING2 (i.e., ING1L) subfamily carries the Q-E-L-G-D-[ED]-K-[ILM]-Q-[IL] motif, the ING4/ING5 (i.e., ING1 homolog) subfamily has the K-E-[FY]-[SG]-D-D-K-V-Q-L motif, the ING3 subfamily is characterized by the L-E-D-A-D-E-K-V-Q-L motif, whereas the generalized large ING subfamily shows a relatively low degree of conservation to any of the above motifs. An exception to this rule is that the three plant ING3 proteins do not bear the L-E-D-A-D-E-K-V-Q-L signature. This region also displays many other conserved residues, signifying its potentially important role. In fact, we have hypothesized that this region of ING proteins involves binding of HAT, HDAC, MYC, and other cell cyclerelated proteins (Helbing et al. 1997), whereas the unique regions of each subfamily member have been suggested to modulate interactions (Kawaji et al. 2002). Kuzmichev et al. (2002) also identified the N-terminal 125 amino acids of p33ING1b, which includes this distinct conserved region, as a motif linked to the Sin3/HDAC complex through direct interaction with SAP30. Therefore, it is becoming increasingly clear that this region of the ING proteins may play a critical role in binding HAT/HDAC complex during chromatin remodeling and regulation of gene expression; hence, the name we propose is the potential chromatin regulatory (PCR) domain (figs. 2 and 3).
The criteria for defining an ING sequence now can include sequence conservation in the first three regions and partially in region IV. Similar to the PCR domain, the PIM (fig. 3, region IV) is also specific for different subfamilies. The distinction between ING1/ING2, ING4/ING5, ING3, and ING subfamilies can be made based on the length of this C-terminal conserved region, because this region in the ING1/ING2 subfamily is considerably longer than the others. The preferential and highly conserved basic residues are indicative of important functions. An additional distinct feature of the ING3 protein is the two insertions of 102 and 54 amino acids located between the PCR domain and the NLS/NTS region (fig. 2A). Although the NLS/NTS region is not as highly conserved across different ING members as the other three defined regions, several lysine residues are preserved (data not shown). As we have postulated before, ING1 and ING2, which have a distinctive NLS/NTS region, are most likely translocated to the nucleolus more efficiently in response to DNA damage but experimental proof of this remains to be presented.
The evolutionary distance of the ING protein members can be estimated from our phylogenetic analysis. We conclude that ING1 and ING2, and ING4 and ING5 are closely related and their chromosomal locations suggest the possibility of duplication of terminal regions of particular chromosome pairs. ING3 on the other hand, is relatively distant from the closely related ING4 and ING5 and the well-related ING 1 and ING2. This may be reflected by ING3s atypical (nontelomeric) location on chromosome 7 and its poorly conserved NLS domain. It may also reflect a more ancestral quality of ING3 in that the distance tree grouped three plant ING3s with Danio rerio, Xenopus, mouse, rat, and human ING3 (fig. 5), which is quite different from the ING1/ING2 and ING4/ING5 group that do not contain plant sequences. The larger Drosophila ING proteins, labeled ING2_Dm, although containing the signature Q-E-L-G-D-[ED]-K-[ILM]-Q-[IL] motif, may not functionally correspond to human ING2, but this remains to be rigorously tested.
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Conclusion |
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Acknowledgements |
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Footnotes |
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References |
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