Synthetic lethality between DNA repair factors Xlf and Paxx is rescued by inactivation of Trp53
| Autor: | Siri Sæterstad, Raquel Gago-Fuentes, Sergio Castañeda-Zegarra, Mengtan Xing, Valentyn Oksenych |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Genome instability
Ku80 DNA Repair DNA repair Synthetic lethality DNA-Activated Protein Kinase Biology LIG4 Biochemistry Cell Line 03 medical and health sciences Gene Knockout Techniques Mice 0302 clinical medicine Animals Humans Gene Silencing Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences DNA ligase Ku70 Nuclear Proteins Cell Biology DNA repair protein XRCC4 Cell biology DNA-Binding Proteins enzymes and coenzymes (carbohydrates) DNA Repair Enzymes chemistry 030220 oncology & carcinogenesis biological phenomena cell phenomena and immunity Tumor Suppressor Protein p53 Synthetic Lethal Mutations |
| Zdroj: | DNA repair. 73 |
| ISSN: | 1568-7856 |
| Popis: | Non-homologous end joining (NHEJ) is a DNA repair pathway that senses, processes and ligates DNA double-strand breaks (DSBs) throughout the cell cycle. During NHEJ, core Ku70 and Ku80 subunits bind DSBs as a heterodimer and promote further recruitment of accessory factors (e.g., PAXX, Mri, DNA-PKcs, Artemis) and downstream core subunits XRCC4 and DNA ligase 4 (Lig4). Inactivation of Ku70 or Ku80 genes in mice results in immunodeficiency and high levels of genomic instability; deletion of individual Dna-pkcs, Xlf, Paxx or Mri genes results in viable mice with no or modest DNA repair defects. However, combined inactivation of either Xlf and Dna-pkcs, or Xlf and Paxx, or Xlf and Mri, leads to synthetic lethality in mice, which correlates with increased levels of apoptosis in the central nervous system. Here, we demonstrated that inactivation of pro-apoptotic factor Trp53 rescues embryonic lethality of Xlf−/−Paxx−/− and Xlf−/−Dna-pkcs−/− double knockout mice. Moreover, combined inactivation of Paxx and Dna-pkcs results in live-born fertile Paxx−/−Dna-pkcs−/− mice indistinguishable from Dna-pkcs−/− knockout controls. |
| Databáze: | OpenAIRE |
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