Disputation: Lise Ellefsen Sandquist
Doctoral candidate Lise Ellefsen Sandquist at the Department of Biosciences will be defending the thesis "Novel mechanisms of DNA damage and replication stress signaling: Functional roles of the WDR82/PNUTS-PP1 phosphatase complex" for the degree of Philosophiae Doctor.
Lise Ellefsen Sandquist
The disputation will be live streamed using Zoom. The host of the session will moderate the technicalities while the chair of the defence will moderate the disputation.
Ex auditorio questions: The chair of the defence will invite the audience to ask ex auditorio questions either written or oral. This can be requested by clicking "Participants" followed by clicking "Raise hand".
The meeting opens for participation just before 1.15 PM, and closes for new participants approximately 15 minutes after the defense has begun.
mTOR signalling pathways in health and disease
Main research findings
Novel mechanisms of DNA damage and replication stress signaling: Functional roles of the WDR82/PNUTS-PP1 phosphatase complex
DNA damaging agents, such as ionizing radiation and many chemotherapeutic drugs, are used in cancer treatment to kill cancer cells. However, networks of signaling cascades induced by DNA damage counteract this by leading to repair of damaged DNA. The ATR kinase is a key component of these signaling networks. We have explored mechanisms of how ATR can be activated. We found that ATR can be activated by phosphorylated RNA polymerase II (RNAPII), the enzyme that reads the DNA code to make messenger RNA in the process of transcription. The RNAPII phosphatase PNUTS-PP1 and two other RNAPII binding proteins, WDR82 and CDC73, were involved in regulating ATR activity. In addition, we found that proper dephosphorylation of RNAPII is important for normal DNA replication since hyperphosphorylated RNAPII is retained on DNA and can cause collisions between RNAPII and the replication machinery. We further explored whether this may sensitize cancer cells to a drug that perturbs DNA replication. Indeed, this drug induced more DNA damage and cell death in cancer cells with reduced levels of WDR82. Altogether our results provide new basic knowledge about DNA damage signaling cascades. This knowledge may potentially be exploited to improve future cancer treatment.