Modifications of p53 and the DNA Damage Response in Cells Expressing Mutant Form of the Protein Huntingtin.

Huntington's disease (HD) occurs through an expansion of the trinucleotide repeat in the HD gene resulting in the lengthening of the polyglutamine stretch within the N terminus of the protein, huntingtin (Htt). While the function of the protein is still being fully elucidated, we have shown that genomic DNA damage ...
is associated with the expression of mutant Htt (mHtt) in a time-dependent fashion. With the accumulation of mHtt and its development into a micro-aggregated complex, the initiation of genomic damage engages a cellular stress signal that activates the DNA damage and stress response pathway. Here we explore the modifications and activation of p53 and keystone regulators of the cell stress response pathway using expression of a fragment of mHtt in HEK293T cells. We find an increase in phosphorylated p53 at serine 15 (S15), diminished acetylation at lysine 382 (K382), altered ubiquitination pattern, and oligomerization activity as a function of mHtt expression. As one might predict, upstream regulators of p53, such as CREB-binding protein/p300 and MDM2, are also seen to be affected by the expression of mHtt, albeit in different ways. These data suggest a possible relationship between p53 and the slow accumulation of DNA damage resulting from the expression of mHtt. The lack of a proper p53-mediated signaling cascade or its alteration in the presence of DNA damage may contribute to the slow progression of cellular dysfunction which is a hallmark of HD pathology.
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Date: Apr. 05, 2011
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