Limits...
An abundant evolutionarily conserved CSB-PiggyBac fusion protein expressed in Cockayne syndrome.

Newman JC, Bailey AD, Fan HY, Pavelitz T, Weiner AM - PLoS Genet. (2008)

Bottom Line: The alternatively spliced mRNA encodes a novel chimeric protein in which CSB exons 1-5 are joined in frame to the PiggyBac transposase.The human genome contains over 600 nonautonomous PGBD3-related MER85 elements that were dispersed when the PGBD3 transposase was last active at least 37 Mya.Many of these MER85 elements are associated with genes which are involved in neuronal development, and are known to be regulated by CSB.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
Cockayne syndrome (CS) is a devastating progeria most often caused by mutations in the CSB gene encoding a SWI/SNF family chromatin remodeling protein. Although all CSB mutations that cause CS are recessive, the complete absence of CSB protein does not cause CS. In addition, most CSB mutations are located beyond exon 5 and are thought to generate only C-terminally truncated protein fragments. We now show that a domesticated PiggyBac-like transposon PGBD3, residing within intron 5 of the CSB gene, functions as an alternative 3' terminal exon. The alternatively spliced mRNA encodes a novel chimeric protein in which CSB exons 1-5 are joined in frame to the PiggyBac transposase. The resulting CSB-transposase fusion protein is as abundant as CSB protein itself in a variety of human cell lines, and continues to be expressed by primary CS cells in which functional CSB is lost due to mutations beyond exon 5. The CSB-transposase fusion protein has been highly conserved for at least 43 Myr since the divergence of humans and marmoset, and appears to be subject to selective pressure. The human genome contains over 600 nonautonomous PGBD3-related MER85 elements that were dispersed when the PGBD3 transposase was last active at least 37 Mya. Many of these MER85 elements are associated with genes which are involved in neuronal development, and are known to be regulated by CSB. We speculate that the CSB-transposase fusion protein has been conserved for host antitransposon defense, or to modulate gene regulation by MER85 elements, but may cause CS in the absence of functional CSB protein.

Show MeSH

Related in: MedlinePlus

Schematic of CSB Mutations Associated with Human Disease.Of 24 patients with known CSB geneotypes and CS, COFS, or XP-DSC phenotypes, 21 have at least one allele that is predicted to express intact CSB-PGBD3 fusion protein. For each patient, the allele with the more C-terminal mutation is shown (e.g. patient CS1AN is a compound heterozygote for K337STOP and del834-866; only the latter is shown here). Some mutations are found in several patients. The location of the homozygous UVsS mutation that causes UV sensitivity but not CS [33] is shown for comparison. See Table S1 for a list of all patients and alleles. fs, frameshift; del, deletion; *, STOP. Red box is the CSB acidic domain; blue boxes are the ATPase subdomains.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2268245&req=5

pgen-1000031-g007: Schematic of CSB Mutations Associated with Human Disease.Of 24 patients with known CSB geneotypes and CS, COFS, or XP-DSC phenotypes, 21 have at least one allele that is predicted to express intact CSB-PGBD3 fusion protein. For each patient, the allele with the more C-terminal mutation is shown (e.g. patient CS1AN is a compound heterozygote for K337STOP and del834-866; only the latter is shown here). Some mutations are found in several patients. The location of the homozygous UVsS mutation that causes UV sensitivity but not CS [33] is shown for comparison. See Table S1 for a list of all patients and alleles. fs, frameshift; del, deletion; *, STOP. Red box is the CSB acidic domain; blue boxes are the ATPase subdomains.

Mentions: Three mysteries have shaped thinking about Cockayne syndrome. First, the complete absence of CSB protein apparently does not cause CS, but rather a mild UV-sensitive syndrome with no developmental symptoms [33]. Yet all disease-associated CSB alleles identified to date are recessive; no dominant mutations are known. Second, nearly all CSB mutations that cause CS are located downstream of the exon 5/6 boundary (codon 466) in the ATPase and C-terminal regions of the 1493 residue protein (Figure 7; see Table S1 for details). And third, mouse models with either a truncating mutation similar to a severe human CSB allele (CS1AN; K337STOP) [55] or a CSA knockout [56] manifest the characteristic UV sensitivity of CS, as well as an unexpected susceptibility to skin cancer not observed for human CSB and CSA mutations, but only a subtle developmental phenotype. However, when the CSB defect is combined with an additional defect in an NER-GGR factor (XPC [57] or XPA [58]), mouse models do recapitulate the full CS-like phenotype including growth retardation, neurological dysfunction, and reduced life span.


An abundant evolutionarily conserved CSB-PiggyBac fusion protein expressed in Cockayne syndrome.

Newman JC, Bailey AD, Fan HY, Pavelitz T, Weiner AM - PLoS Genet. (2008)

Schematic of CSB Mutations Associated with Human Disease.Of 24 patients with known CSB geneotypes and CS, COFS, or XP-DSC phenotypes, 21 have at least one allele that is predicted to express intact CSB-PGBD3 fusion protein. For each patient, the allele with the more C-terminal mutation is shown (e.g. patient CS1AN is a compound heterozygote for K337STOP and del834-866; only the latter is shown here). Some mutations are found in several patients. The location of the homozygous UVsS mutation that causes UV sensitivity but not CS [33] is shown for comparison. See Table S1 for a list of all patients and alleles. fs, frameshift; del, deletion; *, STOP. Red box is the CSB acidic domain; blue boxes are the ATPase subdomains.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2268245&req=5

pgen-1000031-g007: Schematic of CSB Mutations Associated with Human Disease.Of 24 patients with known CSB geneotypes and CS, COFS, or XP-DSC phenotypes, 21 have at least one allele that is predicted to express intact CSB-PGBD3 fusion protein. For each patient, the allele with the more C-terminal mutation is shown (e.g. patient CS1AN is a compound heterozygote for K337STOP and del834-866; only the latter is shown here). Some mutations are found in several patients. The location of the homozygous UVsS mutation that causes UV sensitivity but not CS [33] is shown for comparison. See Table S1 for a list of all patients and alleles. fs, frameshift; del, deletion; *, STOP. Red box is the CSB acidic domain; blue boxes are the ATPase subdomains.
Mentions: Three mysteries have shaped thinking about Cockayne syndrome. First, the complete absence of CSB protein apparently does not cause CS, but rather a mild UV-sensitive syndrome with no developmental symptoms [33]. Yet all disease-associated CSB alleles identified to date are recessive; no dominant mutations are known. Second, nearly all CSB mutations that cause CS are located downstream of the exon 5/6 boundary (codon 466) in the ATPase and C-terminal regions of the 1493 residue protein (Figure 7; see Table S1 for details). And third, mouse models with either a truncating mutation similar to a severe human CSB allele (CS1AN; K337STOP) [55] or a CSA knockout [56] manifest the characteristic UV sensitivity of CS, as well as an unexpected susceptibility to skin cancer not observed for human CSB and CSA mutations, but only a subtle developmental phenotype. However, when the CSB defect is combined with an additional defect in an NER-GGR factor (XPC [57] or XPA [58]), mouse models do recapitulate the full CS-like phenotype including growth retardation, neurological dysfunction, and reduced life span.

Bottom Line: The alternatively spliced mRNA encodes a novel chimeric protein in which CSB exons 1-5 are joined in frame to the PiggyBac transposase.The human genome contains over 600 nonautonomous PGBD3-related MER85 elements that were dispersed when the PGBD3 transposase was last active at least 37 Mya.Many of these MER85 elements are associated with genes which are involved in neuronal development, and are known to be regulated by CSB.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
Cockayne syndrome (CS) is a devastating progeria most often caused by mutations in the CSB gene encoding a SWI/SNF family chromatin remodeling protein. Although all CSB mutations that cause CS are recessive, the complete absence of CSB protein does not cause CS. In addition, most CSB mutations are located beyond exon 5 and are thought to generate only C-terminally truncated protein fragments. We now show that a domesticated PiggyBac-like transposon PGBD3, residing within intron 5 of the CSB gene, functions as an alternative 3' terminal exon. The alternatively spliced mRNA encodes a novel chimeric protein in which CSB exons 1-5 are joined in frame to the PiggyBac transposase. The resulting CSB-transposase fusion protein is as abundant as CSB protein itself in a variety of human cell lines, and continues to be expressed by primary CS cells in which functional CSB is lost due to mutations beyond exon 5. The CSB-transposase fusion protein has been highly conserved for at least 43 Myr since the divergence of humans and marmoset, and appears to be subject to selective pressure. The human genome contains over 600 nonautonomous PGBD3-related MER85 elements that were dispersed when the PGBD3 transposase was last active at least 37 Mya. Many of these MER85 elements are associated with genes which are involved in neuronal development, and are known to be regulated by CSB. We speculate that the CSB-transposase fusion protein has been conserved for host antitransposon defense, or to modulate gene regulation by MER85 elements, but may cause CS in the absence of functional CSB protein.

Show MeSH
Related in: MedlinePlus