Smolinska, Agnieszka Anna
[Verfasser:in]
;
Lerch, Markus M.
[Akademische:r Betreuer:in];
Kleger, Alexander
[Akademische:r Betreuer:in]Universität Greifswald
Role of DNA polymerase theta in the genesis of pancreatic ductal adenocarcinoma
Hochschulschrift:
Dissertation, Universitätsmedizin der Universität Greifswald, 2023
Anmerkungen:
Literaturverzeichnis: Seite 84-97
Zusammenfassung in deutscher Sprache
Beschreibung:
DNA-Polymerase theta, DNA-Reparatur, PDAC, non-homologous end joining, DNA polymerase theta, DNA repair
Pancreatic ductal adenocarcinoma (PDAC), due to its genomic heterogeneity and lack of development of effective therapies, will become the second leading cause of cancer-related death within 10 years. Therefore, identifying novel targets that can predict response to specific treatments is a key goal to personalize pancreatic cancer therapy and improve survival. Given that the occurrence of oncogenic KRAS mutations is a characteristic event in PDAC leading to genome instability, a better understanding of the role of DNA repair mechanisms in this process is desirable. The aim of our study was to investigate the role of the error-prone DNA double strand breaks (DSBs) repair pathway, alt-EJ in the presence of KRAS G12D mutation in pancreatic cancer formation. Our findings showed that oncogenic KRAS contributes to the activation of the alt-EJ mechanism by increasing the expression of Polθ, Lig3 and Mre11, key components of alt-EJ in both mouse and human PDAC models. In addition, we demonstrated that alt-EJ has increased activity in DNA DSBs repair pathway in a mouse and human model of PDAC bearing KRAS G12D mutation. We further focused on estimating the impact of alt-EJ inactivation by polymerase theta (Polθ) deletion on pancreatic cancer development and survival in genetically engineered mouse models (GEMMs). Here, we described that although deficiency of Polθ resulted in delayed cancer progression and prolonged survival of experimental mice, it can lead to full-blown PDAC. Our ...