What role (if any) does the highly conserved CSB-PGBD3 fusion protein play in Cockayne syndrome?
The PGBD3 piggyBac transposon inserted into CSB intron 5 early in the primate lineage. As a result of alternative splicing, the human CSB gene now encodes three proteins: CSB, a CSB-PGBD3 fusion protein that joins the N-terminal CSB domain to the C-terminal PGBD3 transposase domain, and PGBD3 transposase. The fusion protein is as highly conserved as CSB, suggesting that it is advantageous in health; however, expression of the fusion protein in CSB-null cells induces a constitutive interferon (IFN) response. The fusion protein binds in vivo to PGBD3-related MER85 elements, but is also tethered to c-Jun, TEAD1, and CTCF motifs by interactions with the cognate transcription factors. The fusion protein regulates nearby genes from the c-Jun (and to a lesser extent TEAD1 and CTCF) motifs, but not from MER85 elements. We speculate that the fusion protein interferes with CSB-dependent chromatin remodeling, generating double-stranded RNA (dsRNA) that induces an IFN response through endosomal TLR or cytoplasmic RIG-I and/or MDA5 RNA sensors. We suggest that the fusion protein was fixed in primates because an elevated IFN response may help to fight viral infection. We also speculate that an inappropriate IFN response may contribute to the clinical presentation of CS.
Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA 98195-7350, USA. amweiner@uw.edu
Alan M
AM
Weiner
Lucas T
LT
Gray
D017398:Alternative Splicing; D000818:Animals; D042002:Chromatin Assembly and Disassembly; D003057:Cockayne Syndrome / Q000235:genetics / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004251:DNA Transposable Elements; D005786:Gene Expression Regulation; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D007372:Interferons / Q000096:biosynthesis / Q000235:genetics; D007438:Introns; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D012330:RNA, Double-Stranded / Q000096:biosynthesis / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D019895:Transposases / Q000235:genetics / Q000378:metabolism*
D004251:DNA Transposable Elements; D050506:Mutant Chimeric Proteins; C437968:PLAAT4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D012330:RNA, Double-Stranded; D018168:Receptors, Retinoic Acid; D007372:Interferons; D019895:Transposases; C574548:CSB-PGBD3 fusion protein, human; C452815:IFIH1 protein, human; D004265:DNA Helicases; C078673:ERCC6 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D045643:DNA Repair Enzymes