DNA sensing in cancer: Pro-tumour and anti-tumour functions of cGAS-STING signalling.

The DNA sensor cGAS (cyclic GMP-AMP synthase) and its adaptor protein STING (Stimulator of Interferon Genes) detect the presence of cytosolic DNA as a sign of infection or damage. In cancer cells, this pathway can be activated through persistent DNA damage and chromosomal instability, which results in the formation of micronuclei and the exposure of DNA fragments to the cytosol. DNA damage from radio- or chemotherapy can further activate DNA sensing responses, which may occur in the cancer cells themselves or in stromal and immune cells in the tumour microenvironment (TME). cGAS-STING signalling results in the production of type I interferons, which have been linked to immune cell infiltration in 'hot' tumours that are susceptible to immunosurveillance and immunotherapy approaches. However, recent research has highlighted the complex nature of STING signalling, with tumours having developed mechanisms to evade and hijack this signalling pathway for their own benefit. In this mini-review we will explore how cGAS-STING signalling in different cells in the TME can promote both anti-tumour and pro-tumour responses. This includes the role of type I interferons and the second messenger cGAMP in the TME, and the influence of STING signalling on local immune cell populations. We examine how alternative signalling cascades downstream of STING can promote chronic interferon signalling, the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of inflammatory cytokines, which can have pro-tumour functions. An in-depth understanding of DNA sensing in different cell contexts will be required to harness the anti-tumour functions of STING signalling.

Structural Bases of Zoonotic and Zooanthroponotic Transmission of SARS-CoV-2.

The emergence of multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the importance of possible animal-to-human (zoonotic) and human-to-animal (zooanthroponotic) transmission and potential spread within animal species. A range of animal species have been verified for SARS-CoV-2 susceptibility, either in vitro or in vivo. However, the molecular bases of such a broad host spectrum for the SARS-CoV-2 remains elusive. Here, we structurally and genetically analysed the interaction between the spike protein, with a particular focus on receptor binding domains (RBDs), of SARS-CoV-2 and its receptor angiotensin-converting enzyme 2 (ACE2) for all conceivably susceptible groups of animals to gauge the structural bases of the SARS-CoV-2 host spectrum. We describe our findings in the context of existing animal infection-based models to provide a foundation on the possible virus persistence in animals and their implications in the future eradication of COVID-19.