One of the most severe forms of DNA damage is the double-strand break (DSB). Failure to properly repair the damage can cause mutation, gross chromosomal rearrangements and lead to the development of cancer. In eukaryotes, homologous recombination (HR) and non-homologous end joining (NHEJ) are the main DSB repair pathways. Fumarase is a mitochondrial enzyme which functions in the tricarboxylic acid cycle. Intriguingly, the enzyme can be readily detected in the cytosolic compartment of all organisms examined, and we have shown that cytosolic fumarase participates in the DNA damage response towards DSBs. In human cells, fumarase was shown to be involved in NHEJ, but it is still unclear whether fumarase is also important for the HR pathway. Here we show that the depletion of cytosolic fumarase in yeast prolongs the presence of Mre11 at the DSBs, and decreases the kinetics of repair by the HR pathway. Overexpression of Sae2 endonuclease reduced the DSB sensitivity of the cytosolic fumarase depleted yeast, suggesting that Sae2 and fumarase functionally interact. Our results also suggest that Sae2 and cytosolic fumarase physically interact in vivo. Sae2 has been shown to be important for the DSB resection process, which is essential for the repair of DSBs by the HR pathway. Depletion of cytosolic fumarase inhibited DSB resection, while the overexpression of cytosolic fumarase or Sae2 restored resection. Together with our finding that cytosolic fumarase depletion reduces Sae2 cellular amounts, our results suggest that cytosolic fumarase is important for the DSB resection process by regulating Sae2 levels.
Immunotherapies are disease management strategies that target or manipulate components of the immune system. Infectious diseases pose a significant threat to human health as evidenced by countries continuing to grapple with several emerging and re-emerging diseases, the most recent global health threat being the SARS-CoV2 pandemic. As such, various immunotherapeutic approaches are increasingly being investigated as alternative therapies for infectious diseases, resulting in significant advances towards the uncovering of pathogen-host immunity interactions. Novel and innovative therapeutic strategies are necessary to overcome the challenges typically faced by existing infectious disease prevention and control methods such as lack of adequate efficacy, drug toxicity and the emergence of drug resistance. As evidenced by recent developments and success of pharmaceuticals such as monoclonal antibodies, immunotherapies already show abundant promise to overcome such limitations while also advancing the frontiers of medicine. In this review we summarize some of the most notable inroads made to combat infectious disease, over mainly the last 5 years, through the use of immunotherapies such as vaccines, monoclonal antibody-based therapies, T-cell-based therapies, manipulation of cytokine levels and checkpoint inhibition. Whilst its most general applications are founded in cancer treatment, advances made towards the curative treatment of HIV, tuberculosis, malaria, zika virus and, most recently COVID-19, reinforce the role of immunotherapeutic strategies in the broader field of disease control. Ultimately, the comprehensive specificity, safety and cost of immunotherapeutics will impact its widespread implementation.
Antibody–drug conjugates (ADCs) are bifunctional molecules combining the targeting potential of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs. This simple yet intelligently designed system directly addresses the lack of specificity encountered with conventional anti-cancer treatment regimes. However, despite their initial success, the generation of clinically sustainable and effective ADCs has been plagued by poor tumor penetration, undefined chemical linkages, unpredictable pharmacokinetic profiles, and heterogeneous mixtures of products. To this end, we generated a SNAP-tag-based fusion protein targeting the epidermal growth factor receptor (EGFR)a biomarker of aggressive and drug-resistant cancers. Here, we demonstrate the use of a novel click coupling strategy to engineer a benzylguanine (BG)–linker–auristatin F (AuriF) piece that can be covalently tethered to the EGFR-targeting SNAP-tag-based fusion protein in an irreversible 1:1 stoichiometric reaction to form a homogeneous product. Furthermore, using these recombinant ADCs to target EGFR-overexpressing tumor cells, we provide a proof-of-principle for generating biologically active antimitotic therapeutic proteins capable of inducing cell death in a dose-dependent manner, thus alleviating some of the challenges of early ADC development.
Background: Cutaneous malignancies most commonly arise from skin epidermal cells. These cancers may rapidly progress from benign to a metastatic phase. Surgical resection represents the gold standard therapeutic treatment of non-metastatic skin cancer while chemo- and/or radiotherapy are often used against metastatic tumors. However, these therapeutic treatments are limited by the development of resistance and toxic side effects, resulting from passive accumulation of cytotoxic drugs within healthy cells. Objective: This review aims to elucidate how the use of monoclonal antibodies (mAbs) targeting specific tumor associated antigens (TAAs) are paving the way to improved treatment. These mAbs are used as therapeutic or diagnostic carriers that can specifically deliver cytotoxic molecules, fluorophores or radiolabels to cancer cells that overexpress specific target antigens. Results: mAbs raised against TAAs are widely in use for e.g. differential diagnosis, prognosis and therapy of skin cancers. Antibody drug conjugates (ADCs) particularly show remarkable potential. The safest ADCs reported to date use non-toxic photo-activatable photosensitizers (PS), allowing targeted photodynamic therapy (PDT) resulting in targeted delivery of PS into cancer cells and selective killing after light activation without harming the normal cell population. The use of near infrared emitting photosensitizers enables both diagnostic and therapeutic applications upon light activation at the specific wavelengths. Conclusion: Antibody based approaches are presenting an array of opportunities to complement and improve current methods employed for skin cancer diagnosis and treatment.
Breast cancer is characterised by varied responses to different anticancer therapies, which may provoke several different off-target effects. We hypothesise that for drugs that target cell surface receptors (CSRs), the different responses of tumours and the adverse events produced by these drugs may be attributed to variations in the transcriptional landscapes of CSRs in both breast tumours and healthy tissues. Here, we use data from various sources to compare the CSR transcriptional landscapes of breast tumours and a range of different non-diseased human tissues. We demonstrate an association between the responses to drug perturbation of breast cancer cell lines and the transcription levels of their targeted CSRs. Furthermore, we reveal important differences in the CSR transcriptional landscapes of primary breast tumour subtypes and the CSR transcriptional landscapes of breast cancer cell lines, which will likely impact the accuracy of drug response predictions. Finally, applying clinical trial data, we expose a link between the expression levels of CSR genes in healthy tissues and adverse reactions of patients to anticancer drugs. Altogether, this approach allows for the isolation of the most suitable CSR target(s) among the expressed transcripts, solely based on the measured dose-responses of cell lines to small molecules, the CSR transcriptional landscape in health patient tissues, and reported adverse responses of patients to drugs targeting CSRs.
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