Polyglutamine expansion reduces the association of TATA-binding protein with DNA and induces DNA binding-independent neurotoxicity.
TATA-binding protein (TBP) is essential for eukaryotic gene transcription. Human TBP contains a polymorphic polyglutamine (polyQ) domain in its N terminus and a DNA-binding domain in its highly conserved C terminus. Expansion of the polyQ domain to >42 glutamines typically results in spinocerebellar ataxia type 17 (SCA17), a neurodegenerative disorder that resembles Huntington disease. Our recent studies have demonstrated that polyQ expansion causes abnormal interaction of TBP with the general transcription factor TFIIB and induces neurodegeneration in transgenic SCA17 mice (Friedman, M. J., Shah, A. G., Fang, Z. H., Ward, E. G., Warren, S. T., Li, S., and Li, X. J. (2007) Nat. Neurosci. 10, 1519-1528). However, it remains unknown how polyQ expansion influences DNA binding by TBP. Here we report that polyQ expansion reduces in vitro binding of TBP to DNA and that mutant TBP fragments lacking an intact C-terminal DNA-binding domain are present in transgenic SCA17 mouse brains. polyQ-expanded TBP with a deletion spanning part of the DNA-binding domain does not bind DNA in vitro but forms nuclear aggregates and inhibits TATA-dependent transcription activity in cultured cells. When this TBP double mutant is expressed in transgenic mice, it forms nuclear inclusions in neurons and causes early death. These findings suggest that the polyQ tract affects the binding of TBP to promoter DNA and that polyQ-expanded TBP can induce neuronal toxicity independent of its interaction with DNA.
Friedman
Meyer J
MJ
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Wang
Chuan-En
CE
Li
Xiao-Jiang
XJ
Li
Shihua
S
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D011485:Protein Binding; D035181:TATA-Box Binding Protein / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D010455:Peptides; D035181:TATA-Box Binding Protein; C097188:polyglutamine; D004247:DNA