R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage

How DNA damage leads to chronic inflammation and tissue degeneration with aging remains to be fully resolved. Here, we show that DNA damage leads to cellular senescence, fibrosis, loss-of-tissue architecture, and chronic pancreatitis in mice with an inborn defect in the excision repair cross complementation group 1 (Ercc1) gene. We find that DNA damage-driven R-loops causally contribute to the active release and buildup of single-stranded DNAs (ssDNAs) in the cytoplasm of cells triggering a viral-like immune response in progeroid and naturally aged pancreata. To reduce the proinflammatory load, we developed an extracellular vesicle (EV)-based strategy to deliver recombinant S1 or ribonuclease H nucleases in inflamed Ercc1(−/−) pancreatic cells. Treatment of Ercc1(−/−) animals with the EV-delivered nuclease cargo eliminates DNA damage-induced R-loops and cytoplasmic ssDNAs alleviating chronic inflammation. Thus, DNA damage-driven ssDNAs causally contribute to tissue degeneration, Ercc1(−/−) paving the way for novel rationalized intervention strategies against age-related chronic inflammation

XPF interacts with TOP2B for R-loop processing and DNA looping on actively transcribed genes

Co-transcriptional RNA-DNA hybrids can not only cause DNA damage threatening genome integrity but also regulate gene activity in a mechanism that remains unclear. Here, we show that the nucleotide excision repair factor XPF interacts with the insulator binding protein CTCF and the cohesin subunits SMC1A and SMC3, leading to R-loop-dependent DNA looping upon transcription activation. To facilitate R-loop processing, XPF interacts and recruits with TOP2B on active gene promoters, leading to double-strand break accumulation and the activation of a DNA damage response. Abrogation of TOP2B leads to the diminished recruitment of XPF, CTCF, and the cohesin subunits to promoters of actively transcribed genes and R-loops and the concurrent impairment of CTCF-mediated DNA looping. Together, our findings disclose an essential role for XPF with TOP2B and the CTCF/cohesin complex in R-loop processing for transcription activation with important ramifications for DNA repair-deficient syndromes associated with transcription-associated DNA damage

Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage

DNA damage and metabolic disorders are intimately linked with premature disease onset but the underlying mechanisms remain poorly understood. Here, we show that persistent DNA damage accumulation in tissue-infiltrating macrophages carrying an ERCC1-XPF DNA repair defect (Er1(F/-)) triggers Golgi dispersal, dilation of endoplasmic reticulum, autophagy and exosome biogenesis leading to the secretion of extracellular vesicles (EVs) in vivo and ex vivo. Macrophage-derived EVs accumulate in Er1(F/-) animal sera and are secreted in macrophage media after DNA damage. The Er1(F/-) EV cargo is taken up by recipient cells leading to an increase in insulin-independent glucose transporter levels, enhanced cellular glucose uptake, higher cellular oxygen consumption rate and greater tolerance to glucose challenge in mice. We find that high glucose in EV-targeted cells triggers pro-inflammatory stimuli via mTOR activation. This, in turn, establishes chronic inflammation and tissue pathology in mice with important ramifications for DNA repair-deficient, progeroid syndromes and aging

Proteases of haematophagous arthropod vectors are involved in blood-feeding, yolk formation and immunity : a review

Ticks, triatomines, mosquitoes and sand flies comprise a large number of haematophagous arthropods considered vectors of human infectious diseases. While consuming blood to obtain the nutrients necessary to carry on life functions, these insects can transmit pathogenic microorganisms to the vertebrate host. Among the molecules related to the blood-feeding habit, proteases play an essential role. In this review, we provide a panorama of proteases from arthropod vectors involved in haematophagy, in digestion, in egg development and in immunity. As these molecules act in central biological processes, proteases from haematophagous vectors of infectious diseases may influence vector competence to transmit pathogens to their prey, and thus could be valuable targets for vectorial control

Improved reference genome of Aedes aegypti informs arbovirus vector control

Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector

The ideological frame of the genetic basis of cancer: The important role of mirnas

The elucidation of the genetic basis of cancer is the result of the research conducted since the beginning of the previous century, which peaked during the decades of 1960s and 1970s. It has been achieved through two different but convergent routes: the first includes the study of oncogenic viruses in rodents and birds and the second includes the use of chemical carcinogens in cells or in animal model systems (mice). Within this framework, the identification of genes that present mutations, alterations in expression levels, and epigenetic modifications has been facilitated through the development of animal carcinogenesis models. One of these models is the well-characterized mouse multistage skin cancer system discussed in this review. In addition, recent evidence shows the great significance that cancer stem cells seem to have in the emergence and progression of carcinogenesis. Finally, herein we discuss the critical role that miRNAs have emerged to play in cancer progression. miRNAs emerged as molecules with an impact on most cancer-related cellular processes, involving cell proliferation, cell death (apoptosis), angiogenesis, migration/motility,and rearrangement of the cytoskeleton. Their discovery has given rise to studies with a focus on miRNAs as key players in crucial oncogenesis-related processes and thus as potential targets in cancer therapeutics. © 2017 by Begell House, Inc

The COVID‑19 pandemic as a scientific and social challenge in the 21st century

The coronavirus disease-2019 (coVid-19) pandemic, caused by the new coronavirus SarS-coV-2, has spread around the globe with unprecedented consequences for the health of millions of people. While the pandemic is still in progress, with new incidents being reported every day, the resilience of the global society is constantly being challenged. under these circumstances, the future seems uncertain. SarS-coV-2 coronavirus has spread panic among civilians and insecurity at all socio-political and economic levels, dramatically disrupting everyday life, global economy, international travel and trade. The disease has also been linked to the onset of depression in many individuals due to the extreme restriction measures that have been taken for the prevention of the rapid spreading of coVid-19. First, the socio-economic, political and psychological implications of the coVid-19 pandemic were explored. Substantial evidence is provided for the consequences of the pandemic on all aspects of everyday life, while at the same time we unravel the role and the pursuits of national regimes during this unforeseen situation. The second goal of this review is related to the scientific aspect of the pandemic. Hence, we explain why SarS-coV-2 is not a so-called ‘invisible enemy’, and also attempt to give insight regarding the origin of the virus, in an effort to reject the conspiracy theories that have arisen during the pandemic. Finally, rational strategies were investigated for successful vaccine development. We are optimistic that this review will complement the knowledge of specialized scientists and inform non‑specialized readers on basic scientific questions, and also on the social and economic implications of the coVid-19 pandemic. © 2020 Spandidos Publications. All rights reserved

Targeted Deletion of a Plasmodium Site-2 Protease Impairs Life Cycle Progression in the Mammalian Host

Site-2 proteases (S2P) belong to the M50 family of metalloproteases, which typically perform essential roles by mediating activation of membrane-bound transcription factors through regulated intramembrane proteolysis (RIP). Protease-dependent liberation of dormant transcription factors triggers diverse cellular responses, such as sterol regulation, Notch signalling and the unfolded protein response. Plasmodium parasites rely on regulated proteolysis for controlling essential pathways throughout the life cycle. In this study we examine the Plasmodium-encoded S2P in a murine malaria model and show that it is expressed in all stages of Plasmodium development. Localisation studies by endogenous gene tagging revealed that in all invasive stages the protein is in close proximity to the nucleus. Ablation of PbS2P by reverse genetics leads to reduced growth rates during liver and blood infection and, hence, virulence attenuation. Strikingly, absence of PbS2P was compatible with parasite life cycle progression in the mosquito and mammalian hosts under physiological conditions, suggesting redundant or dispensable roles in vivo