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The DUB/USP17 deubiquitinating enzymes: a gene family within a tandemly repeated sequence, is also embedded within the copy number variable beta-defensin cluster.

Burrows JF, Scott CJ, Johnston JA - BMC Genomics (2010)

Bottom Line: Here we demonstrate that the human DUB/USP17 family members are found on both chromosome 4p16.1, within a block of tandem repeats, and on chromosome 8p23.1, embedded within the copy number variable beta-defensin cluster.However, it is also apparent when sequences from humans and the more closely related chimpanzee are compared, that duplication events have taken place prior to these species separating.In addition, their presence within the beta-defensin repeat raises the question whether they may contribute to the influence of this repeat on immune related conditions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Faculty of Medicine, Health and Life Sciences, Queen's University, Belfast, Northern Ireland. j.burrows@qub.ac.uk

ABSTRACT

Background: The DUB/USP17 subfamily of deubiquitinating enzymes were originally identified as immediate early genes induced in response to cytokine stimulation in mice (DUB-1, DUB-1A, DUB-2, DUB-2A). Subsequently we have identified a number of human family members and shown that one of these (DUB-3) is also cytokine inducible. We originally showed that constitutive expression of DUB-3 can block cell proliferation and more recently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the 'CAAX' box protease RCE1.

Results: Here we demonstrate that the human DUB/USP17 family members are found on both chromosome 4p16.1, within a block of tandem repeats, and on chromosome 8p23.1, embedded within the copy number variable beta-defensin cluster. In addition, we show that the multiple genes observed in humans and other distantly related mammals have arisen due to the independent expansion of an ancestral sequence within each species. However, it is also apparent when sequences from humans and the more closely related chimpanzee are compared, that duplication events have taken place prior to these species separating.

Conclusions: The observation that the DUB/USP17 genes, which can influence cell growth and survival, have evolved from an unstable ancestral sequence which has undergone multiple and varied duplications in the species examined marks this as a unique family. In addition, their presence within the beta-defensin repeat raises the question whether they may contribute to the influence of this repeat on immune related conditions.

Show MeSH
Phylogenetic tree of primate DUB/USP17 family members. Phylogenetic tree of representative chimpanzee and human DUB/USP17 DNA sequences generated using a ClustalW2 alignment. The species of origin of each sequence is identified by the brackets and the accompanying labels. The chromosome of origin of the chimpanzee sequences is indicated within the brackets adjacent to the loci number. The sequence accession numbers can be found in Additional file 9.
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Figure 6: Phylogenetic tree of primate DUB/USP17 family members. Phylogenetic tree of representative chimpanzee and human DUB/USP17 DNA sequences generated using a ClustalW2 alignment. The species of origin of each sequence is identified by the brackets and the accompanying labels. The chromosome of origin of the chimpanzee sequences is indicated within the brackets adjacent to the loci number. The sequence accession numbers can be found in Additional file 9.

Mentions: Finally, we examined sequences from other primates and found 10 sequences in Pan troglodytes (chimpanzee) on chromosomes 4 (GenBank: NC_006471) (LOC750726, LOC750728, LOC750731), 8 (GenBank: NC_006475)(LOC735845, LOC736589), 11 (GenBank: NC_006478) (LOC748110, LOC748210, LOC748219), and 12 (GenBank: NC_006479)(LOC748408, LOC749572) that are potential DUB/USP17 genes. However, only 4 of these contained intact ORFs (LOC750726, LOC735845, LOC748110, LOC748210), and when these were aligned with other family members only 2 contained all the key residues necessary for catalytic activity (LOC748110, LOC748210) (Additional file 8). We also identified 1 sequence from macaca mulatta (rhesus monkey) chromosome 8 (GenBank: NC_007865) (LOC695235) which had an intact ORF and when we examined pongei abelii (Sumatran orang-utan) we found several genomic clones from chromosome 8 which contain an unresolved tandem repeat equivalent to RS447. Indeed, we found one BAC clone (GenBank: AC210623) which has more than 20 tandemly repeated copies, many of which contain intact ORFs. When the predicted proteins from both of these were aligned with other family members they are intact and potentially active. We created a phylogenetic tree examining the relationship between the sequences from Pan troglodytes and humans (Figure 6). Unlike our previous comparisons, it was evident that the human and Pan troglodytes sequences do not segregate and it would appear that there may well have been several common ancestral sequences prior to these two species separating. It is also interesting that the sequences from the different Pan troglodytes chromosomes are spread between the different blocks of similarity, suggesting they may have resulted from the duplication of a block of sequences from one chromosome onto another, rather than the tandem duplication of a sequence once it has been transferred to that chromosome. This is similar to what is observed on human chromosome 8. It is also interesting to note that we observed beta-defensin genes in close proximity to the sequences on Pan troglodytes chromosomes 4, 8 and 11 as well as Macaca mulatta chromosome 8 (data not shown).


The DUB/USP17 deubiquitinating enzymes: a gene family within a tandemly repeated sequence, is also embedded within the copy number variable beta-defensin cluster.

Burrows JF, Scott CJ, Johnston JA - BMC Genomics (2010)

Phylogenetic tree of primate DUB/USP17 family members. Phylogenetic tree of representative chimpanzee and human DUB/USP17 DNA sequences generated using a ClustalW2 alignment. The species of origin of each sequence is identified by the brackets and the accompanying labels. The chromosome of origin of the chimpanzee sequences is indicated within the brackets adjacent to the loci number. The sequence accession numbers can be found in Additional file 9.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874809&req=5

Figure 6: Phylogenetic tree of primate DUB/USP17 family members. Phylogenetic tree of representative chimpanzee and human DUB/USP17 DNA sequences generated using a ClustalW2 alignment. The species of origin of each sequence is identified by the brackets and the accompanying labels. The chromosome of origin of the chimpanzee sequences is indicated within the brackets adjacent to the loci number. The sequence accession numbers can be found in Additional file 9.
Mentions: Finally, we examined sequences from other primates and found 10 sequences in Pan troglodytes (chimpanzee) on chromosomes 4 (GenBank: NC_006471) (LOC750726, LOC750728, LOC750731), 8 (GenBank: NC_006475)(LOC735845, LOC736589), 11 (GenBank: NC_006478) (LOC748110, LOC748210, LOC748219), and 12 (GenBank: NC_006479)(LOC748408, LOC749572) that are potential DUB/USP17 genes. However, only 4 of these contained intact ORFs (LOC750726, LOC735845, LOC748110, LOC748210), and when these were aligned with other family members only 2 contained all the key residues necessary for catalytic activity (LOC748110, LOC748210) (Additional file 8). We also identified 1 sequence from macaca mulatta (rhesus monkey) chromosome 8 (GenBank: NC_007865) (LOC695235) which had an intact ORF and when we examined pongei abelii (Sumatran orang-utan) we found several genomic clones from chromosome 8 which contain an unresolved tandem repeat equivalent to RS447. Indeed, we found one BAC clone (GenBank: AC210623) which has more than 20 tandemly repeated copies, many of which contain intact ORFs. When the predicted proteins from both of these were aligned with other family members they are intact and potentially active. We created a phylogenetic tree examining the relationship between the sequences from Pan troglodytes and humans (Figure 6). Unlike our previous comparisons, it was evident that the human and Pan troglodytes sequences do not segregate and it would appear that there may well have been several common ancestral sequences prior to these two species separating. It is also interesting that the sequences from the different Pan troglodytes chromosomes are spread between the different blocks of similarity, suggesting they may have resulted from the duplication of a block of sequences from one chromosome onto another, rather than the tandem duplication of a sequence once it has been transferred to that chromosome. This is similar to what is observed on human chromosome 8. It is also interesting to note that we observed beta-defensin genes in close proximity to the sequences on Pan troglodytes chromosomes 4, 8 and 11 as well as Macaca mulatta chromosome 8 (data not shown).

Bottom Line: Here we demonstrate that the human DUB/USP17 family members are found on both chromosome 4p16.1, within a block of tandem repeats, and on chromosome 8p23.1, embedded within the copy number variable beta-defensin cluster.However, it is also apparent when sequences from humans and the more closely related chimpanzee are compared, that duplication events have taken place prior to these species separating.In addition, their presence within the beta-defensin repeat raises the question whether they may contribute to the influence of this repeat on immune related conditions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Faculty of Medicine, Health and Life Sciences, Queen's University, Belfast, Northern Ireland. j.burrows@qub.ac.uk

ABSTRACT

Background: The DUB/USP17 subfamily of deubiquitinating enzymes were originally identified as immediate early genes induced in response to cytokine stimulation in mice (DUB-1, DUB-1A, DUB-2, DUB-2A). Subsequently we have identified a number of human family members and shown that one of these (DUB-3) is also cytokine inducible. We originally showed that constitutive expression of DUB-3 can block cell proliferation and more recently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the 'CAAX' box protease RCE1.

Results: Here we demonstrate that the human DUB/USP17 family members are found on both chromosome 4p16.1, within a block of tandem repeats, and on chromosome 8p23.1, embedded within the copy number variable beta-defensin cluster. In addition, we show that the multiple genes observed in humans and other distantly related mammals have arisen due to the independent expansion of an ancestral sequence within each species. However, it is also apparent when sequences from humans and the more closely related chimpanzee are compared, that duplication events have taken place prior to these species separating.

Conclusions: The observation that the DUB/USP17 genes, which can influence cell growth and survival, have evolved from an unstable ancestral sequence which has undergone multiple and varied duplications in the species examined marks this as a unique family. In addition, their presence within the beta-defensin repeat raises the question whether they may contribute to the influence of this repeat on immune related conditions.

Show MeSH