CLASS 1 Flashcards
What are bacterial genotoxins?
Bacterial genotoxins are toxins produced by bacteria that cause direct or indirect damage to the host cell’s DNA, leading to mutations, genomic instability, or cellular senescence.
Name the three main bacterial genotoxins studied in relation to cancer.
The three main bacterial genotoxins are:
Cytolethal Distending Toxins (CDTs)
Colibactin
Typhoid Toxin
Which bacterial genotoxin is associated with Salmonella Typhimurium?
Typhoid toxin is associated with Salmonella Typhimurium.
How do bacterial genotoxins contribute to cancer?
Bacterial genotoxins induce DNA damage that can lead to:
Mutations and genomic instability.
Cellular senescence, creating a pro-tumorigenic microenvironment.
Chronic inflammation, which can promote tumor initiation and progression.
How do Cytolethal Distending Toxins (CDTs) cause DNA damage?
CDTs function as a DNase, directly cleaving host DNA to induce double-strand breaks, leading to cell cycle arrest, apoptosis, or senescence.
What is the primary role of colibactin in bacterial pathogenesis?
Colibactin, produced by some strains of Escherichia coli, causes DNA interstrand crosslinks, which are particularly difficult to repair, contributing to genomic instability.
What is unique about the typhoid toxin’s structure and function?
Typhoid toxin has a heterotrimeric structure, including DNase activity that targets host DNA and a unique ability to modulate the host immune response to enhance bacterial survival and persistence.
How does cellular senescence induced by genotoxins contribute to cancer?
Senescent cells secrete pro-inflammatory cytokines, growth factors, and proteases (collectively termed the senescence-associated secretory phenotype or SASP), which can promote tumor growth and alter the tissue microenvironment.
Which host DNA repair mechanisms are involved in responding to bacterial genotoxin-induced damage?
The two primary mechanisms are:
Homologous recombination (HR): Repairs double-strand breaks using a homologous DNA template (requires BRCA1/BRCA2).
Base excision repair (BER): Repairs single-strand breaks (involves PARP-1).
Why might individuals with BRCA1/BRCA2 mutations be more susceptible to genotoxin-induced cancer?
BRCA1/BRCA2 mutations impair homologous recombination, making it difficult to repair genotoxin-induced double-strand breaks, leading to increased genomic instability and cancer risk.
How can PARP inhibitors be used in the context of genotoxin-related cancer?
PARP inhibitors prevent the repair of single-strand breaks, causing replication fork collapse and double-strand breaks, which are lethal in cells with defective HR repair, such as those with BRCA1/BRCA2 mutations.
How does chronic bacterial infection contribute to cancer risk?
Chronic bacterial infection leads to sustained inflammation, DNA damage from reactive oxygen and nitrogen species, and dysbiosis, creating a tumor-promoting environment.
What role does dysbiosis play in bacterial genotoxin-induced cancer?
Dysbiosis disrupts the gut microbial balance, increasing colonization by genotoxin-producing bacteria and reducing the protective microbial populations, which exacerbates inflammation and DNA damage.
Can genotoxins influence the immune response?
Yes, genotoxins can modulate the immune response by inducing senescence-associated inflammation (SASP) and evading immune detection, promoting bacterial persistence and tumor development.
What experimental models are commonly used to study bacterial genotoxins?
In vivo models: Genotoxin-producing bacteria in animal models to study inflammation, tumor initiation, and progression.
3D organotypic tissue cultures: Immune-competent systems mimicking host tissues to clarify molecular mechanisms.
Why is Salmonella Typhimurium considered a valuable model for studying genotoxins?
Salmonella Typhimurium produces typhoid toxin, a well-characterized genotoxin, and is the only genotoxin-producing bacterium directly associated with human cancer.
How can targeting bacterial genotoxins contribute to cancer prevention?
Strategies to prevent genotoxin-induced cancer include:
Early eradication of genotoxin-producing bacteria using antibiotics.
Development of vaccines targeting genotoxin-producing bacteria.
Modulating the microbiome to reduce genotoxin-producing populations.
How can CTC research complement studies on bacterial genotoxins?
CTC phenotyping can identify biomarkers of DNA damage (e.g., γH2AX) induced by genotoxins.
CTC functional studies can assess the tumorigenic potential of cells exposed to genotoxins.
What are the future implications of bacterial genotoxin research?
Identification of genotoxin-induced cancer biomarkers for early diagnosis.
Personalized therapies targeting genotoxin-affected DNA repair pathways.
Probiotic and microbiome therapies to reduce genotoxin-associated dysbiosis.
What are the current challenges in studying bacterial genotoxins?
Complexity of the gut microenvironment, including diverse microbiota and host interactions.
Difficulty in isolating the specific contribution of genotoxins to cancer amidst other factors.
Limited understanding of the long-term effects of genotoxins on host cells and tissues.
