Proteotoxic stress can result in the accumulation of misfolded proteins within the cell that need to be stabilised and refolded by chaperonin proteins. Failure to carry out this response efficiently can lead to the formation of protein aggregates and tangles that may play a role in the initiation of events that lead to neurological disease. Previously we have performed quantitative proteomic analyses of SUMO-2 substrates after proteotoxic stress induced by heat or after short- and long-term inhibition of the proteasome with MG132. Comparisons of changes to the SUMO-2 conjugate subproteome between the two conditions revealed qualitative and quantitative parallels between heat stress and proteasome inhibition (Tatham et al., 2011). SUMO site mapping (Tammsalu et al., 2014) and cellular fractionation experiments suggest that after proteotoxic stress most of the SUMO modified substrates are chromatin associated. The objective of the proposed project will to carry out Chromatin Immuno Precipitation linked to high throughput sequencing (ChIPSeq) analysis to define the genomic landscape of SUMO modification in response to proteotoxic stress and establish the role of chromatin associated SUMO modification.
1. Comparative proteomic analysis identifies a role for SUMO in protein quality control. Tatham MH, Matic I, Mann M, Hay RT. Sci Signal. 2011 Jun 21;4(178):rs4. doi: 10.1126/scisignal.2001484. PMID:21693764 (Read online)
2. Proteome-wide identification of SUMO2 modification sites. Tammsalu T, Matic I, Jaffray EG, Ibrahim AF, Tatham MH, Hay RT. Sci Signal. 2014 Apr 29;7(323):rs2. doi: 10.1126/scisignal.2005146. PMID: 24782567