Peter Stirling

Associate Professor

Research Classification

Molecular Genetics
Biological and Biochemical Mechanisms
Cancer Genetics
Cell

Research Interests

Genome Instability
Stress responses
DNA repair
Cancer
Genotoxins

Relevant Degree Programs

 

Research Methodology

Yeast
Genomics
Microscopy
cell culture
DNA repair

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Doctoral students
Postdoctoral Fellows
2019
I support public scholarship, e.g. through the Public Scholars Initiative, and am available to supervise students and Postdocs interested in collaborating with external partners as part of their research.
I am open to hosting Visiting International Research Students (non-degree, up to 12 months).
I am interested in hiring Co-op students for research placements.

Great Supervisor Week Mentions

Each year graduate students are encouraged to give kudos to their supervisors through social media and our website as part of #GreatSupervisorWeek. Below are students who mentioned this supervisor since the initiative was started in 2017.

 

Here's to @pcstirling for supporting all of us, challenging us, and making us better scientists everyday!

Stirling Lab (2017)

 

Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
Genome instability in multiple myeloma-associated DIS3 exonuclease domain mutants (2019)

Chromosome instability (CIN) is characterized by an increased rate of the unequal distribution of DNA between daughter cells. Such changes in chromosome structure or number can occur due to both mitotic defects leading to aneuploidy and DNA damage-induced chromosome rearrangements. Previous large-scale screens for CIN genes in the model organism Saccharomyces cerevisiae identified DIS3, which encodes a catalytic component of the core RNA exosome complex, as a novel CIN gene. Mutations in human DIS3 have been identified in roughly 11% of multiple myeloma (MM) cases. I sought to recapitulate MM-associated point mutations at conserved sites in yeast cells, in order to understand the mechanism of emergent CIN in MM. I have found that MM-associated DIS3 exonuclease mutations do increase the frequency of CIN. A temperature sensitive DIS3 mutant accumulates DNA:RNA hybrids, however analysis of DNA damage foci by microscopy revealed no increase in double-strand breaks in any of the tested strains. Yeast DIS3 exonuclease mutants experience growth retardation, temperature sensitivity, and an altered cell cycle. Microarray analysis of one MM mutant has additionally demonstrated downregulation of cell cycle components, consistent with the potential for mitotic defects, in addition of upregulation of a host of metabolic pathways. Further, genetic interaction profiling by synthetic genetic array indicates MM-associated DIS3 mutations synthetically interact with rRNA processing proteins, as well as a host of mitotic regulators and metabolic pathways, particularly those involved in spindle and kinetochore function. Further, I verify that DIS3 mutants have a functional spindle assembly checkpoint, and are in fact resistant to microtubule poisons. Finally, I discover that the fitness defects induced by these mutations can be abrogated through culturing on media containing only a non-fermentable carbon source, suggesting that growth on poor carbon sources may also rescue CIN.Together, these results demonstrate extensive phenotypic consequences of MM-associated point mutations in DIS3, and support a model for CIN in DIS3 mutants involving defects in mitotic progression.

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Master's Student Supervision (2010 - 2018)
Synthetic hypermutation : gene-drug mutation rate synergy reveals a translesion synthesis mechanism (2017)

Gene-gene or gene-drug interactions are typically quantified using fitness as a readout because the data is continuous and easily measured in high-throughput. However, to what extent fitness captures the range of other phenotypes that show synergistic effects is usually unknown. Using Saccharomyces cerevisiae, and focusing on a matrix of DNA repair mutants and genotoxic drugs, I quantified 76 gene-drug interactions based on both mutation rate and fitness and find that these parameters are not connected. Independent of fitness defects I identified seven cases of synthetic hypermutation, where the combined effect of the drug and mutant on mutation rate was greater than predicted. One example occurred when yeast lacking RAD1 were exposed to cisplatin and I characterized this interaction using whole-genome sequencing. Our sequencing results indicate mutagenesis by cisplatin in rad1∆ cells depended almost entirely on interstrand crosslinks at GpCpN motifs. Interestingly, our data suggest that the 3’ base in this motif templates the addition of the mutated base. This result differs from cisplatin mutation signatures in XPF-deficient C. elegans and supports a model in which translesion synthesis polymerases perform a slippage and realignment extension across from the damaged base. Accordingly, DNA polymerase zeta activity was essential for mutagenesis in cisplatin-treated rad1∆ cells. Together these data reveal the potential to gain new mechanistic insights from non-fitness measures of gene-drug interactions and extend the use of mutation accumulation and whole-genome sequencing analysis to define DNA repair mechanisms.

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Publications

 
 

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