Sub-lethal activation of the caspase-activated DNAse contributes to genomic instability and tumorigenesis during infection and inflammation

Abstract: Chronic inflammation and infections are epidemiologically linked to carcinogenesis. It is well known that patients suffering from inflammatory bowel disease have a higher risk to develop colorectal cancer. Further, many microbial infections are associated or related to initial lesions that may contribute to cancerogenesis. However, the potentially underlying mechanisms remain partly unclear. Besides well-known pathogens like Helicobacter pylori and human papillomavirus (HPV), other pathogens like Salmonella Typhimurium and Chlamydia trachomatis are less prominently associated with carcinogenesis. An insult to the host cell that may link pathogens, chronic inflammation and subsequent cancer development is introduction of genomic mutations. Recent studies of apoptosis (a form of programmed cell death) found a limited activation of apoptosis signals that however did not lead to cell death. On the one hand, this low-level activation may serve as a cell autonomous defence mechanism. On the other hand, it implicates a detrimental risk. The induction of DNA-damage can facilitate mutagenesis in surviving cells. Therefore sub-lethal apoptotic signalling is an interesting candidate as a mechanism of genomic instability and tumorigenesis.
This study focused on the sub-lethal activation of the caspase-activated DNase (CAD) and its consequences. Main objective of this work was to understand whether CAD plays a role in generating genomic instability and thus may contribute to tumorigenesis during infection and inflammation. Two prominent mediators of inflammation, TNF (tumour necrosis factor) and IFN-β (interferon-β) were shown to induce substantial DNA-damage and a DNA-damage response, in a CAD-dependent manner. Strikingly, the high-risk human papillomavirus (HPV) oncogenes E6 and E7 were also found to introduce genomic instability at least partially through sub-lethal CAD signalling. Furthermore, the mutagenic potential of IFN-β and Salmonella Typhimurium was assessed with the HPRT (hypoxanthine-guanine phosphoribosyltransferase)-mutation assay and revealed a robust CAD-dependent generation of mutated cells. The mutagenic potential of Chlamydia trachomatis remained inconclusive in this experimental setup.
Lastly, a next-generation sequencing approach was used to map CAD-induced double-strand breaks genome-wide. The sequencing unravelled distinct cleavage of DNA by CAD, significantly associated with CTCF (CCCTC-binding factor) and AP-1 (activator-protein-1) family transcription factor motifs. Moreover, a high proportion of cleavage sites was located in gene regions. The presented study highlights a potential involvement of limited CAD activity in DNA-damage and subsequent transformation in the context of infection and inflammation in vitro. It provides new insights on the activity and consequences of caspase-activated DNase signalling and opens up new directions to further investigate and understand the process of sub-lethal apoptotic signals

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2021

Classification and Topics

• Keyword: Apoptosis ; Signaltransduktion ; Apoptosis

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2022
• Creator: Gregg, Julia
• Contributor: Häcker, Georg ; Süss, Regine ; Häcker, Georg ; Institut für Medizinische Mikrobiologie und Hygiene. Freiburg im Breisgau ; Albert-Ludwigs-Universität Freiburg. Fakultät für Chemie und Pharmazie

Further information

• DOI: 10.6094/UNIFR/223924
• URN: urn:nbn:de:bsz:25-freidok-2239245
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:47 PM CET