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The cytoplasmic DNA sensor cGAS detects DNA in ruptured micronuclei and activates an innate immune response. Autoimmunity under surveillance Innate immune activation has been implicated in autoimmunity and cancer. Here, Andrew Jackson and colleagues provide evidence for an underlying mechanism whereby ruptured micronuclei, which result from endogenous or exogenous chromosomal damage, activate a cell-autonomous inflammatory response via the cytoplasmic DNA sensor cGAS. They conclude that cGAS recognition of micronuclei may be acting as a kind of immune surveillance system in cells. Elsewhere in this issue, Roger Greenberg and colleagues report a link between mitosis and DNA-damage-induced inflammatory signalling involving cGAS in cancer cells. DNA is strictly compartmentalized within the nucleus to prevent autoimmunity 1 ; despite this, cyclic GMP–AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage 2 , 3 , 4 , 5 , 6 . Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis 7 , leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes.

The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well‐established clinical guidelines. Physicians are often forced to engage in cycles of “trial and error” that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are “aging faster” to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine. Finding a reference metric for the rate of biological aging is key to understanding the molecular nature of the aging process. Defining and validating this metric in humans opens the door to a new kind of medicine that will overcome the limitation of current disease definitions. We will then be able to approach health in a global perspective and bring life course preventative measures to the center of attention.

DNA and RNA can adopt various secondary structures. Four-stranded G-quadruplex (G4) structures form through self-recognition of guanines into stacked tetrads, and considerable biophysical and structural evidence exists for G4 formation in vitro. Computational studies and sequencing methods have revealed the prevalence of G4 sequence motifs at gene regulatory regions in various genomes, including in humans. Experiments using chemical, molecular and cell biology methods have demonstrated that G4s exist in chromatin DNA and in RNA, and have linked G4 formation with key biological processes ranging from transcription and translation to genome instability and cancer. In this Review, we first discuss the identification of G4s and evidence for their formation in cells using chemical biology, imaging and genomic technologies. We then discuss possible functions of DNA G4s and their interacting proteins, particularly in transcription, telomere biology and genome instability. Roles of RNA G4s in RNA biology, especially in translation, are also discussed. Furthermore, we consider the emerging relationships of G4s with chromatin and with RNA modifications. Finally, we discuss the connection between G4 formation and synthetic lethality in cancer cells, and recent progress towards considering G4s as therapeutic targets in human diseases.G-quadruplexes (G4s) are structures formed in guanine-rich DNA or RNA, which are linked to transcription, translation, chromatin biology, genome instability and RNA modifications. Recent studies connect G4 formation with cancer-cell lethality and indicate that G4s could be therapeutic targets.

Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Similar results were obtained with multiple strains of 13 additional cell lines. Notably, genetic changes were associated with differential activation of gene expression programs and marked differences in cell morphology and proliferation. Barcoding experiments showed that cell line evolution occurs as a result of positive clonal selection that is highly sensitive to culture conditions. Analyses of single-cell-derived clones demonstrated that continuous instability quickly translates into heterogeneity of the cell line. When the 27 MCF7 strains were tested against 321 anti-cancer compounds, we uncovered considerably different drug responses: at least 75% of compounds that strongly inhibited some strains were completely inactive in others. This study documents the extent, origins and consequences of genetic variation within cell lines, and provides a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research. The extent, origins and consequences of genetic variation within human cell lines are studied, providing a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.

Common fragile sites (CFSs) are loci that are hypersensitive to replication stress and hotspots for chromosomal rearrangements in cancers. CFSs replicate late in S phase, are cell-type specific and nest in large genes. The relative impact of transcription–replication conflicts versus a low density in initiation events on fragility is currently debated. Here we addressed the relationships between transcription, replication, and instability by manipulating the transcription of endogenous large genes in chicken and human cells. We found that inducing low transcription with a weak promoter destabilized large genes, whereas stimulating their transcription with strong promoters alleviated instability. Notably, strong promoters triggered a switch to an earlier replication timing, supporting a model in which high transcription levels give cells more time to complete replication before mitosis. Transcription could therefore contribute to maintaining genome integrity, challenging the dominant view that it is exclusively a threat.

All living things are remarkably complex, yet their DNA is unstable, undergoing countless random mutations over generations. Despite this instability, most animals do not grow two heads or die, plants continue to thrive, and bacteria continue to divide.Robustness and Evolvability in Living Systemstackles this perplexing paradox. The book explores why genetic changes do not cause organisms to fail catastrophically and how evolution shapes organisms' robustness. Andreas Wagner looks at this problem from the ground up, starting with the alphabet of DNA, the genetic code, RNA, and protein molecules, moving on to genetic networks and embryonic development, and working his way up to whole organisms. He then develops an evolutionary explanation for robustness. Wagner shows how evolution by natural selection preferentially finds and favors robust solutions to the problems organisms face in surviving and reproducing. Such robustness, he argues, also enhances the potential for future evolutionary innovation. Wagner also argues that robustness has less to do with organisms having plenty of spare parts (the redundancy theory that has been popular) and more to do with the reality that mutations can change organisms in ways that do not substantively affect their fitness. Unparalleled in its field, this book offers the most detailed analysis available of all facets of robustness within organisms. It will appeal not only to biologists but also to engineers interested in the design of robust systems and to social scientists concerned with robustness in human communities and populations.

Defining the transition from benign to malignant tissue is fundamental to improving early diagnosis of cancer 1 . Here we use a systematic approach to study spatial genome integrity in situ and describe previously unidentified clonal relationships. We used spatially resolved transcriptomics 2 to infer spatial copy number variations in >120,000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue using an organ-wide approach focused on the prostate. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of capturing the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy. Copy number variations inferred from spatial transcriptomics data in benign and malignant tissue reveal clonal architecture at the organ-wide level.

Key Points Termination of DNA replication occurs when two replication forks meet on the same stretch of DNA, during which the following events occur, although not necessarily in this order: forks converge until all intervening DNA is unwound; any remaining gaps are filled and ligated; catenanes are removed; and replication proteins are unloaded. In eukaryotes, most termination sites are determined stochastically by the location of replication initiation sites. In bacteria, termination generally occurs at a specific locus. Replication termination can be a problematic process. Termination of simian virus 40 (SV40) replication involves the stalling of converging forks, and bacterial termination is prone to inducing re-replication. By contrast, fork stalling or re-replication have not been observed during unperturbed termination in eukaryotes. Topological stress accumulates between converging forks and is relieved by the generation of pre-catenanes, which are removed by type II topoisomerases. During bacterial and SV40 termination, type II topoisomerases are required for fork convergence, but in eukaryotes they are dispensable for this purpose. After forks converge, any remaining catenanes are removed by a type II topoisomerase. In eukaryotes, gaps are readily filled by the extension of the leading strands, but in bacteria and SV40 this process is less well-defined. In eukaryotes, a dedicated replisome removal pathway has recently been identified, which operates late during termination, after the DNA is fully replicated. It is unclear whether any comparable pathway exists in bacteria. The termination of DNA replication involves convergence of replication forks, the completion of DNA synthesis, replisome disassembly and the decatenation of daughter DNA molecules. Recent discoveries illustrate how replisome disassembly in eukaryotes is controlled by E3 ubiquitin ligases and how this activity is regulated to avoid genome instability. Genome duplication is carried out by pairs of replication forks that assemble at origins of replication and then move in opposite directions. DNA replication ends when converging replication forks meet. During this process, which is known as replication termination, DNA synthesis is completed, the replication machinery is disassembled and daughter molecules are resolved. In this Review, we outline the steps that are likely to be common to replication termination in most organisms, namely, fork convergence, synthesis completion, replisome disassembly and decatenation. We briefly review the mechanism of termination in the bacterium Escherichia coli and in simian virus 40 (SV40) and also focus on recent advances in eukaryotic replication termination. In particular, we discuss the recently discovered E3 ubiquitin ligases that control replisome disassembly in yeast and higher eukaryotes, and how their activity is regulated to avoid genome instability.

Developing novel targeted anticancer therapies is a major goal of current research. The use of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with homologous recombination-deficient tumours provides one of the best examples of a targeted therapy that has been successfully translated into the clinic. The success of this approach has so far led to the approval of four different PARP inhibitors for the treatment of several types of cancers and a total of seven different compounds are currently under clinical investigation for various indications. Clinical trials have demonstrated promising response rates among patients receiving PARP inhibitors, although the majority will inevitably develop resistance. Preclinical and clinical data have revealed multiple mechanisms of resistance and current efforts are focused on developing strategies to address this challenge. In this Review, we summarize the diverse processes underlying resistance to PARP inhibitors and discuss the potential strategies that might overcome these mechanisms such as combinations with chemotherapies, targeting the acquired vulnerabilities associated with resistance to PARP inhibitors or suppressing genomic instability.Poly(ADP-ribose) polymerase (PARP) inhibitors are approved for patients with several forms of cancer, predominantly those harbouring loss-of-function BRCA1/2 mutations or other homologous recombination defects. Nonetheless, most patients receiving PARP inhibitors will ultimately develop resistance to PARP inhibitors, resulting in disease progression. In this Review, the authors describe the mechanisms of resistance to PARP inhibitors and discuss the potential treatment strategies that might overcome these effects.

Cancer research relies on model systems, which reflect the biology of actual human tumours to only a certain extent. One important feature of human cancer is its intra-tumour genomic heterogeneity and instability. However, the extent of such genomic instability in cancer models has received limited attention in research. Here, we review the state of knowledge of genomic instability of cancer models and discuss its biological origins and implications for basic research and for cancer precision medicine. We discuss strategies to cope with such genomic evolution and evaluate both the perils and the emerging opportunities associated with it.