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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.

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Human DUB/USP17 family members. Representative diagrams of (A) chromosome 4 (GRCh37 primary reference assembly [GenBank: NC_000004]) from bases 9,200,000 to base 9,400,000 and (B) chromosome 8 (GRCh37 primary reference assembly [GenBank: NC_000008]) from bases 7,185,000 to 7,205,000, 7,820,000 to 7,840,000 and 11,980,000 to 12,000,000. The approximate position of the identified human DUB/USP17 sequences are indicated by the boxes illustrated and the appropriate loci numbers are indicated adjacent. (C) Phylogenetic tree of the identified human DUB/USP17 DNA sequences generated using a ClustalW2 alignment. The chromosome of origin is indicated by the brackets and accompanying labels. The sequence accession numbers can be found in Additional file 8.
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Figure 1: Human DUB/USP17 family members. Representative diagrams of (A) chromosome 4 (GRCh37 primary reference assembly [GenBank: NC_000004]) from bases 9,200,000 to base 9,400,000 and (B) chromosome 8 (GRCh37 primary reference assembly [GenBank: NC_000008]) from bases 7,185,000 to 7,205,000, 7,820,000 to 7,840,000 and 11,980,000 to 12,000,000. The approximate position of the identified human DUB/USP17 sequences are indicated by the boxes illustrated and the appropriate loci numbers are indicated adjacent. (C) Phylogenetic tree of the identified human DUB/USP17 DNA sequences generated using a ClustalW2 alignment. The chromosome of origin is indicated by the brackets and accompanying labels. The sequence accession numbers can be found in Additional file 8.

Mentions: We searched the available databases for human genomic sequences which could represent members of the DUB/USP17 family. Then, concentrating on the current human genome assembly (GRCh37 primary reference assembly) we have identified and mapped all potential family members. Thirty-two separate loci were found to represent potential members of this family on both chromosomes 4 and 8 (Figure 1A and 1B). On chromosome 4p16.1 (GenBank: NC_0000004)(Figure 1A) we found two separate blocks of RS447 tandem repeats consisting of 13 and 10 copies respectively. Closer examination revealed that these blocks were in fact separated by an assembly gap suggesting these sequences represent a portion of a single block of tandem repeats which has not been fully resolved due to its repetitive nature. On chromosome 8p23.1 (GenBank: NC_0000008)(Figure 1B) we identified 3 blocks of 3 RS447 repeat units. Upon further analysis of the sequences on chromosome 4 we found that 20 of the 23 sequences contained an intact ORF of 1593 bp equivalent to those previously identified (USP17, DUB-3) [6,10] and that the previously identified USP17 was one of the sequences present. On chromosome 8 we found that 6 of the 9 sequences had intact ORFs and that DUB-3 was one of the sequences present.


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)

Human DUB/USP17 family members. Representative diagrams of (A) chromosome 4 (GRCh37 primary reference assembly [GenBank: NC_000004]) from bases 9,200,000 to base 9,400,000 and (B) chromosome 8 (GRCh37 primary reference assembly [GenBank: NC_000008]) from bases 7,185,000 to 7,205,000, 7,820,000 to 7,840,000 and 11,980,000 to 12,000,000. The approximate position of the identified human DUB/USP17 sequences are indicated by the boxes illustrated and the appropriate loci numbers are indicated adjacent. (C) Phylogenetic tree of the identified human DUB/USP17 DNA sequences generated using a ClustalW2 alignment. The chromosome of origin is indicated by the brackets and accompanying labels. The sequence accession numbers can be found in Additional file 8.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Human DUB/USP17 family members. Representative diagrams of (A) chromosome 4 (GRCh37 primary reference assembly [GenBank: NC_000004]) from bases 9,200,000 to base 9,400,000 and (B) chromosome 8 (GRCh37 primary reference assembly [GenBank: NC_000008]) from bases 7,185,000 to 7,205,000, 7,820,000 to 7,840,000 and 11,980,000 to 12,000,000. The approximate position of the identified human DUB/USP17 sequences are indicated by the boxes illustrated and the appropriate loci numbers are indicated adjacent. (C) Phylogenetic tree of the identified human DUB/USP17 DNA sequences generated using a ClustalW2 alignment. The chromosome of origin is indicated by the brackets and accompanying labels. The sequence accession numbers can be found in Additional file 8.
Mentions: We searched the available databases for human genomic sequences which could represent members of the DUB/USP17 family. Then, concentrating on the current human genome assembly (GRCh37 primary reference assembly) we have identified and mapped all potential family members. Thirty-two separate loci were found to represent potential members of this family on both chromosomes 4 and 8 (Figure 1A and 1B). On chromosome 4p16.1 (GenBank: NC_0000004)(Figure 1A) we found two separate blocks of RS447 tandem repeats consisting of 13 and 10 copies respectively. Closer examination revealed that these blocks were in fact separated by an assembly gap suggesting these sequences represent a portion of a single block of tandem repeats which has not been fully resolved due to its repetitive nature. On chromosome 8p23.1 (GenBank: NC_0000008)(Figure 1B) we identified 3 blocks of 3 RS447 repeat units. Upon further analysis of the sequences on chromosome 4 we found that 20 of the 23 sequences contained an intact ORF of 1593 bp equivalent to those previously identified (USP17, DUB-3) [6,10] and that the previously identified USP17 was one of the sequences present. On chromosome 8 we found that 6 of the 9 sequences had intact ORFs and that DUB-3 was one of the sequences present.

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