This week we profile a recent publication in The Journal of Cell Biology from (right to left)
Dr. Peter Stirling, Karissa Milbury, Annie Tam, and Veena Mathew at Terry Fox Laboratories.
Can you provide a brief overview of your lab’s current research focus?
My lab is broadly interested in how cells faithfully replicate, repair and segregate their DNA in order to prevent mutations. We want to know how defects in these processes contribute to mutagenesis during cancer development and how such defects might influence the cellular response to stresses such as genotoxic chemotherapies.
What is the significance of the findings in this publication?
When a cell responds to DNA damage it must coordinate DNA repair with changes in both the transcriptome and proteome that together promote recovery and stress tolerance. Using a yeast model, this study identified a new way cells regulate gene expression under stress, namely, by disassembling a splicing complex called SF3B, and sequestering one of its core subunits in a nuclear protein aggregate, blocking gene expression at a post-transcriptional step. This sequestration behaviour blocked splicing and promoted efficient recovery from stress by helping to shut-down the energetically costly production of ribosomes. It is one of the first studies to describe a purposeful fate for proteins evicted from DNA during stress-induced remodelling of the gene expression landscape.
What are the next steps for this research?
This work suggests that several proteins ejected from chromatin following stress are sequestered in protein aggregates to promote cell survival. Currently we are addressing how this is regulated by mapping post-translational chemical modifications of the proteins themselves in hopes of finding a switch that is induced by stress. Human cells also sequester proteins in aggregates under stress, and we are actively investigating the role of a highly conserved protein called p97/Cdc48, which we have since discovered is likely to be regulating the formation of these aggregates. p97 inhibitors are in phase I clinical trials for treatment of solid tumours and we think it is an ideal candidate gene to begin translating our findings across species. Ultimately interventions which impair a cancer cells ability to respond to stress should sensitize them to conventional therapies.
This research was funded by:
Canadian Institutes of Health Research
Natural Sciences and Engineering Council of Canada
