Increasing evidence demonstrates that DNA damage and genome instability play a crucial role in ageing. Mammalian cells have developed a wide range of complex and well‐orchestrated DNA repair pathways ...to respond to and resolve many different types of DNA lesions that occur from exogenous and endogenous sources. Defects in these repair pathways lead to accelerated or premature ageing syndromes and increase the likelihood of cancer development. Understanding the fundamental mechanisms of DNA repair will help develop novel strategies to treat ageing‐related diseases. Here, we revisit the processes involved in DNA damage repair and how these can contribute to diseases, including ageing and cancer. We also review recent mechanistic insights into DNA repair and discuss how these insights are being used to develop novel therapeutic strategies for treating human disease. We discuss the use of PARP inhibitors in the clinic for the treatment of breast and ovarian cancer and the challenges associated with acquired drug resistance. Finally, we discuss how DNA repair pathway‐targeted therapeutics are moving beyond PARP inhibition in the search for ever more innovative and efficacious cancer therapies.
In this review, we revisit the processes involved in DNA damage repair and how these can contribute to diseases, including ageing and cancer. We also review recent mechanistic insights into DNA repair and discuss how these insights are being used to develop novel therapeutic strategies for treating human disease.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic that has infected over 36 million and killed over 1 million people. Informed implementation of ...government public health policies depends on accurate data on SARS-CoV-2 immunity at a population scale. We hypothesized that detection of SARS-CoV-2 salivary antibodies could serve as a noninvasive alternative to serological testing for monitoring of SARS-CoV-2 infection and seropositivity at a population scale. We developed a multiplex SARS-CoV-2 antibody immunoassay based on Luminex technology that comprised 12 CoV antigens, mostly derived from SARS-CoV-2 nucleocapsid (N) and spike (S). Saliva and sera collected from confirmed coronavirus disease 2019 (COVID-19) cases and from the pre-COVID-19 era were tested for IgG, IgA, and IgM to the antigen panel. Matched saliva and serum IgG responses (
= 28) were significantly correlated. The salivary anti-N IgG response resulted in the highest sensitivity (100%), exhibiting a positive response in 24/24 reverse transcription-PCR (RT-PCR)-confirmed COVID-19 cases sampled at >14 days post-symptom onset (DPSO), whereas the salivary anti-receptor binding domain (RBD) IgG response yielded 100% specificity. Temporal kinetics of IgG in saliva were consistent with those observed in blood and indicated that most individuals seroconvert at around 10 DPSO. Algorithms employing a combination of the IgG responses to N and S antigens result in high diagnostic accuracy (100%) by as early as 10 DPSO. These results support the use of saliva-based antibody testing as a noninvasive and scalable alternative to blood-based antibody testing.
Resveratrol: Friend or Foe? Clarke, Thomas L.; Mostoslavsky, Raul
Molecular cell,
09/2020, Letnik:
79, Številka:
5
Journal Article
Recenzirano
Odprti dostop
In this issue of Molecular Cell, Benslimane et al. (2020) perform a CRISPR-Cas9 chemogenomic screen, identifying a network of DNA replication and genome integrity genes with the nutraceutical ...compound Resveratrol and its analog Pterostilbene, linking these compounds to the induction of DNA replication stress in mammalian cells.
In this issue of Molecular Cell, Benslimane et al. (2020) perform a CRISPR-Cas9 chemogenomic screen, identifying a network of DNA replication and genome integrity genes with the nutraceutical compound Resveratrol and its analog Pterostilbene, linking these compounds to the induction of DNA replication stress in mammalian cells.
Protein post-translation modification plays an important role in regulating DNA repair; however, the role of arginine methylation in this process is poorly understood. Here we identify the arginine ...methyltransferase PRMT5 as a key regulator of homologous recombination (HR)-mediated double-strand break (DSB) repair, which is mediated through its ability to methylate RUVBL1, a cofactor of the TIP60 complex. We show that PRMT5 targets RUVBL1 for methylation at position R205, which facilitates TIP60-dependent mobilization of 53BP1 from DNA breaks, promoting HR. Mechanistically, we demonstrate that PRMT5-directed methylation of RUVBL1 is critically required for the acetyltransferase activity of TIP60, promoting histone H4K16 acetylation, which facilities 53BP1 displacement from DSBs. Interestingly, RUVBL1 methylation did not affect the ability of TIP60 to facilitate ATM activation. Taken together, our findings reveal the importance of PRMT5-mediated arginine methylation during DSB repair pathway choice through its ability to regulate acetylation-dependent control of 53BP1 localization.
Display omitted
•PRMT5 is a regulator of homologous recombination-mediated double-strand break repair•PRMT5 methylates RUVBL1 at R205, regulating TIP60-mediated histone acetylation•Loss of RUVBL1 methylation leads to 53BP1 retention at break ends•Arginine methylation crosstalks with histone acetylation to regulate repair pathway choice
Clarke et al. show that methylation of RUVBL1 by the arginine methyltransferase PRMT5 is required for homologous recombination-mediated double-strand break repair by promoting TIP60-mediated histone H4K16 acetylation. Loss of PRMT5 activity and defective RUVBL1 methylation leads to 53BP1 retention, increased sensitivity to DNA damaging agents, and genome instability.
Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for ...BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population.
Display omitted
•PRMT5 expression is elevated in breast cancer stem cells (BCSCs)•PRMT5 is required for BCSC function and self-renewal in vitro and in vivo•Targeting PRMT5 in an established tumor reduces stem cell numbers and tumor growth•FOXP1 promoter is methylated by PRMT5 and is an effector of PRMT5-driven BCSC function
Chiang et al. show that the arginine methyltransferase PRMT5 contributes to breast cancer stem cell function, in part through histone methylation regulating FOXP1 expression. Targeting of PRMT5 through depletion or inhibition reduces stem cell frequency in vitro and in vivo, implicating PRMT5 as important in breast cancer pathogenesis.
Zinc finger proteins (ZNF), a unique yet diverse group of proteins, play pivotal roles in fundamental cellular mechanisms including transcription regulation, chromatin remodeling, protein/RNA ...homeostasis, and DNA repair. Consequently, the mis regulation of ZNF proteins can result in a variety of human diseases, ranging from neurodevelopmental disorders to several cancers. Considering the promising results of DNA damage repair (DDR) inhibition in the clinic, as a therapeutic strategy for patients with homologous recombination (HR) deficiency, identifying other potential targetable DDR proteins as emerged vulnerabilities in resistant tumor cells is essential, especially when considering the burden of acquired drug resistance. Importantly, there are a growing number of studies identifying new ZNFs and revealing their significance in several DDR pathways, highlighting their great potential as new targets for DDR-inhibition therapy. Although, there are still many uncharacterized ZNF-containing proteins with unknown biological function. In this review, we highlight the major classes and observed biological functions of ZNF proteins in mammalian cells. We briefly introduce well-known and newly discovered ZNFs and describe their molecular roles and contributions to human health and disease, especially cancer. Finally, we discuss the significance of ZNFs in DNA repair mechanisms, their potential in cancer therapy and advances in exploiting ZNF proteins as future therapeutic targets for human disease.
Warming increases the metabolic rates of fishes and drives their oxygen demands above environmental oxygen supply, leading to declines in fish growth and smaller population sizes. Given the wide ...variability in species' sensitivity to changing temperature and oxygen levels, warming and oxygen limitation may be altering the composition of fish communities and hence, that of fisheries catches. Here, we test the hypothesis that changing temperatures shape the composition of pelagic fisheries catches in the Eastern Tropical Pacific. We expect that under warmer conditions, pelagic fisheries catches will be dominated by tropical species with higher oxygen demands and less surplus oxygen for growth. To test this hypothesis, we combined an index of the physiological vulnerability of exploited large pelagic fishes (e.g. tuna and billfish) to changing ocean temperatures and oxygen levels with fisheries catch data from 1970 to 2016. We found that warming is the main driver of changes in the physiological performance and catch composition of this fishery, and that oxygen limitation may be causing a significant breakpoint in the relationship between sea surface oxygen and the index of vulnerability of pelagic catches in the Ecuador and Galapagos Exclusive Economic Zones. Warm temperature anomalies due to El Niño were projected to cause reductions in the physiological performance of large pelagic fishes, although this only led to changes in catch composition during the extremely warm events. Our results suggest that catches are vulnerable to future warming, as the increasing frequency, duration and magnitude of marine heatwaves associated with climate change impact catch composition.
•AGI projects the effects of ocean warming and deoxygenation on species biogeography.•AGI links species growth and metabolism to ambient temperature and oxygen.•AGI is a ratio of oxygen supply to ...demand that can project species habitat loss.•AGI replicates the output of physiologically derived metabolic indices.
Ocean warming and deoxygenation are affecting the physiological performance of marine species by increasing their oxygen demand while reducing oxygen supply. Impacts on organisms (e.g., growth and reproduction) can eventually affect entire populations, altering macroecological dynamics and shifting species’ distribution ranges. To quantify the effect of warming and deoxygenation on marine organisms, Penn et al. (2018) and Deutsch et al. (2020) developed two metabolic indices that integrate physiological, biogeographic and climatic data. Here, we develop an alternative index, referred to as Aerobic Growth Index (AGI) based on an approach that integrates the von Bertalanffy growth and metabolic theory. We compare the results derived from the application of AGI with those of the two previously published metabolic indices for six species: Atlantic blue crab (Callinectes sapidus), sharpsnout seabream (Diplodus puntazzo), Atlantic cod (Gadus morhua), Australian spiny lobster (Panulirus cygnus), red drum (Sciaenops ocellatus) and common cuttlefish (Sepia officinalis). The baseline (1971–2000) habitat suitability values of AGI are significantly and positively correlated with both metabolic indices (R2 ≥ 0.92). All three indices also show similar spatial patterns and magnitudes of viable habitat loss by the end of the 21st century (2071–2100) relative to baseline conditions under a high greenhouse gas trajectory (Representative Concentration Pathway 8.5). Our results support the applicability and use of AGI to better understand the impacts of warming and deoxygenation on global marine fishery resources. Given the uncertainties surrounding mechanisms linking temperature, oxygen and biogeography, there is a need for different indicators to account for these uncertainties in climate change projections.
Rebuilding overexploited marine populations is an important step to achieve the United Nations' Sustainable Development Goal 14—Life Below Water. Mitigating major human pressures is required to ...achieve rebuilding goals. Climate change is one such key pressure, impacting fish and invertebrate populations by changing their biomass and biogeography. Here, combining projection from a dynamic bioclimate envelope model with published estimates of status of exploited populations from a catch‐based analysis, we analyze the effects of different global warming and fishing levels on biomass rebuilding for the exploited species in 226 marine ecoregions of the world. Fifty three percent (121) of the marine ecoregions have significant (at 5% level) relationship between biomass and global warming level. Without climate change and under a target fishing mortality rate relative to the level required for maximum sustainable yield of 0.75, we project biomass rebuilding of 1.7–2.7 times (interquartile range) of current (average 2014–2018) levels across marine ecoregions. When global warming level is at 1.5 and 2.6°C, respectively, such biomass rebuilding drops to 1.4–2.0 and 1.1–1.5 times of current levels, with 10% and 25% of the ecoregions showing no biomass rebuilding, respectively. Marine ecoregions where biomass rebuilding is largely impacted by climate change are in West Africa, the Indo‐Pacific, the central and south Pacific, and the Eastern Tropical Pacific. Coastal communities in these ecoregions are highly dependent on fisheries for livelihoods and nutrition security. Lowering the targeted fishing level and keeping global warming below 1.5°C are projected to enable more climate‐sensitive ecoregions to rebuild biomass. However, our findings also underscore the need to resolve trade‐offs between climate‐resilient biomass rebuilding and the high near‐term demand for seafood to support the well‐being of coastal communities across the tropics.
Rebuilding overexploited marine populations is an important step to achieve the United Nations' Sustainable Development Goal 14—Life Below Water. Using climate‐ocean‐fish population model for the world’s marine ecoregions to study rebuilding fish populations under climate change, we project that global warming levels at or above 1.5°C substantially reduce the amount of rebuildable fish biomass. Such warming levels may even prohibit any biomass rebuilding in climate‐sensitive but fisheries‐dependent tropical regions. Our findings also underscore the need to resolve the trade‐offs between climate‐resilient biomass rebuilding and the high near‐term demand for seafood to support the well‐being of coastal communities across the tropics.
PDF
