Investigating the role scaffold attachment factors play in the stress response

Abstract

Scientific Abstract As cells are accustomed to their surroundings, any disturbance can thus be regarded as a stressor. A protective stress response is produced by all cells upon exposure to a wide variety of stressors, including high temperatures, ischaemia, and osmotic shock. The cellular stress response is characterized by the inhibition of standard cellular transcription and translation, and the production of heat shock proteins. These proteins protect the cells from degradation, primarily by preventing irregular protein folding and aggregation and through mediating the anti-apoptotic effects. Heat shock factor 1 (HSF1), a key heat shock transcription factor, is critical in the stress response. Through its interaction with satellite III DNA sequences in the pericentromeric regions of human chromosomes, HSF1 has been implicated in altering the transcription of noncoding sequences. Specific RNA binding proteins and transcription factors can be recruited to the scaffold region formed by Satellite III transcripts. Nuclear stress bodies (aSBs) are named after the scaffold regions in the cells, and are thought to regulate transcriptional halting, modulate gene expression, and support RNA splicing. The Scaffold Attachment Factor B (SAFB) protein, a member of the RBP family, has been linked to transcriptional regulation, RNA processing, and regulation of the stress response. Cells exposed to stress, HSF1, and SAFB proteins were hypothesized to regulate transcription and result in alternative splicing processes respectively, due to their colocalization with nuclear stress bodies (nSBs). Thus, the principal objective of this study is to identify the functional domains of SAFB2 involved in recruitment of nSBs. Lay Abstract Cells must be protected from factors that affect their stability and capacity to perform their functions correctly. The cell acts to defend itself when exposed to any risk factor, such as high temperatures, osmotic pressure, or damage to the cellular membrane; these factors are referred to as stress factors. The cell responds to stressors by inhibiting the transcription of 11 genes, or preventing the formation of proteins not naturally present within the cell, initiating the programmed death of the cell where required to avoid complications. The HSF1 protein is one of the essential proteins allowing the cell to respond effectively to stressors, by regulating gene expression. The HSF1 protein accumulates in areas called scaffold regions that have unique nuclear structures called nuclear stress bodies. These cellular bodies are believed to play a role in gene expression and RNA processing. Scaffold Attachment Factor B (SAFB) proteins are parts of the RNA binding protein family and are thought to contribute to the control of RNA processing and stress responses. Some polyglutamine disorders, such as Huntington's and cerebellar ataxias, have high levels of SAFB protein expression, because of a failure to establish a full stress response. It has been suggested that HSF1) and SAFB proteins, which are colocalized with the nSBs in stressed cells, control the transcription and alternative splicing of RNA respectively. This research thus explores which parts of the SAFB2 protein are responsible for the formation of nuclear stress bodies.