Detection of microbial DNA is an evolutionarily conserved mechanism that alerts the host immune system to mount a defense response to microbial infections. However, this detection mechanism also poses a challenge to the host as to how to distinguish foreign DNA from abundant self-DNA. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is a DNA sensor that triggers innate immune responses through production of the second messenger cyclic GMP-AMP (cGAMP), which binds and activates the adaptor protein STING. However, cGAS can be activated by double-stranded DNA irrespective of the sequence, including self-DNA. Although how cGAS is normally kept inactive in cells is still not well understood, recent research has provided strong evidence that genomic DNA damage leads to cGAS activation to stimulate inflammatory responses. This review summarizes recent findings on how genomic instability and DNA damage trigger cGAS activation and how cGAS serves as a link from DNA damage to inflammation, cellular senescence, and cancer.

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The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer.

Engineered nanoparticles (NPs) are widely used in different technologies but their unique properties might also cause adverse health effects. In reviewing recent in vitro and in vivo genotoxicity studies we discuss potential mechanisms of genotoxicity induced by NPs. Various factors that may influence genotoxic response, including physico-chemical properties and experimental conditions, are highlighted. From 4346 articles on NP toxicity, 112 describe genotoxicity studies (94 in vitro, 22 in vivo). The most used assays are the comet assay (58 in vitro, 9 in vivo), the micronucleus assay (31 in vitro, 14 in vivo), the chromosome aberrations test (10 in vitro, 1 in vivo) and the bacterial reverse mutation assay (13 studies). We describe advantages and potential problems with different methods and suggest the need for appropriate methodologies to be used for investigation of genotoxic effects of NPs, in vitro and in vivo.

Mechanisms of genotoxicity. A review of in vitro and in vivo studies with engineered nanoparticles.

Over a century ago, Theodor Boveri paved the way to mechanistic studies linking chromosomal abnormalities to cancer pathogenesis. Since then, theoretical and empirical evidence has been accumulated, supporting a causal role of these events in the aetiology of human cancer. A powerful tool for measurement of chromosomal abnormalities is the cytokinesis-block micronucleus cytome (CBMNcyt) assay. The validation of the micronucleus (MN) as marker of phenotypic susceptibility to cancer has received decisive support from mutagens sensitivity studies, particularly from a recent case-control study on lung cancer, which showed increased frequency of tobacco carcinogen-induced MN, nuclear buds and especially nucleoplasmic bridges in cancer patients (odds ratios of 2.3, 10.0 and 45.5, respectively). Recently, a large international cohort study showed a significant association between MN frequency in healthy subjects and cancer risk. The study assembled data on 6718 individuals from 10 countries (62 980 person-years). Cancers incidence was significantly higher in groups with medium (RR = 1.84; 95% confidence interval: 1.28-2.66) and high MN frequency (RR = 1.53; 95% CI: 1.04-2.25). This study provided preliminary evidence that MN frequency in peripheral blood lymphocytes is predictive of cancer risk, suggesting that increased MN formation is associated with early events in carcinogenesis. These results, in combination with mechanistic evidence, prospected the use of MN frequency in cancer screening programmes. However, issues such as interindividual variability and preventive strategies in high-risk groups need to be further addressed to consolidate these achievements.

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Micronuclei frequency in peripheral blood lymphocytes and cancer risk: evidence from human studies

Genomic alterations that lead to oncogene activation and tumour suppressor loss are important driving forces for cancer development. Although these changes can accumulate progressively during cancer evolution, recent studies have revealed that many cancer cells harbour chromosomes bearing tens to hundreds of clustered genome rearrangements. In this Review, we describe how this striking phenomenon, termed chromothripsis, is likely to arise through chromosome breakage and inaccurate reassembly. We also discuss the potential diagnostic, prognostic and therapeutic implications of chromothripsis in cancer.

Chromothripsis and cancer: causes and consequences of chromosome shattering

The emerging role of cell-free DNA as a molecular marker for cancer management.

Micronuclei (MN) and other nuclear anomalies such as nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) are biomarkers of genotoxic events and chromosomal instability. These genome damage events can be measured simultaneously in the cytokinesis-block micronucleus cytome (CBMNcyt) assay. The molecular mechanisms leading to these events have been investigated over the past two decades using molecular probes and genetically engineered cells. In this brief review, we summarise the wealth of knowledge currently available that best explains the formation of these important nuclear anomalies that are commonly seen in cancer and are indicative of genome damage events that could increase the risk of developmental and degenerative diseases. MN can originate during anaphase from lagging acentric chromosome or chromatid fragments caused by misrepair of DNA breaks or unrepaired DNA breaks. Malsegregation of whole chromosomes at anaphase may also lead to MN formation as a result of hypomethylation of repeat sequences in centromeric and pericentromeric DNA, defects in kinetochore proteins or assembly, dysfunctional spindle and defective anaphase checkpoint genes. NPB originate from dicentric chromosomes, which may occur due to misrepair of DNA breaks, telomere end fusions, and could also be observed when defective separation of sister chromatids at anaphase occurs due to failure of decatenation. NBUD represent the process of elimination of amplified DNA, DNA repair complexes and possibly excess chromosomes from aneuploid cells.

J. W. Crott

Papers

Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells