Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases

Nature cell biology, March 2007

Speaker：傅孝瑜               Time: 2007/10/17 15:10~16:00

Commentator：劉校生 老師      Place: Room601

Abstract：

Polyglutamine(PolyQ) disorders (such as Spinocerebellar ataxia type 1,  Huntington’s disease and so on) are hereditary diseases involve extra expanded stretchs of consecutive CAG trinucleotides that add glutamines to the protein products¹. The mutant polyQ proteins (AT1 or Htt) resulting in neuron degeneration were suggested to impair the function of nuclear factors by directly interaction. The authors find the expression of high mobility group B1/2 (HMGB1/2) is obviously reduced in polyQdiseases from 200 candidate proteins with quantitative changes by proteomics approach. Immunoprecipitation and pulldown assays indicate that mutant polyQ proteins interact and co-localize with HMGB1/2. HMGB1 and HMGB2 are abundant in all mammalian nuclei and homologues are found in all eukaryotes. Recent findings suggest that HMGB proteins are involved in DNA repair mechenism². Similar function is identified in this article that HGMB1/2 suppress the genotoxic stress signals (such as p73 and p53) triggered by mutant AT1 or Htt through transcription repression. Furthermore, in Drosophila models, complementation of HMGB1 ameliorates toxicity of mutant polyQ proteins. Thus, HMGB1/2 may play an important role in the symptom control and therapy of polyQ disease.

Reference：

1.         Gusella, J. F. et al. Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nature Rev. Neurosci, 1, 109–115 (2000).

2.         Ohndorf, U.-M. et al. Basis for recognition of cisplatin-modified DNA by high mobility group proteins. Nature 399, 708–712(1999).