Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous ...cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity.
The Lancet Commission on pollution and health Landrigan, Philip J; Fuller, Richard; Acosta, Nereus J R ...
The Lancet (British edition),
02/2018, Letnik:
391, Številka:
10119
Journal Article
Recenzirano
Odprti dostop
Fuel combustion-fossil fuel combustion in high-income and middle-income countries and burning of biomass in low-income countries-accounts for 85% of airborne particulate pollution and for almost all ...pollution by oxides of sulphur and nitrogen. ...ambient air pollution, chemical pollution, and soil pollution-the forms of pollution produced by industry, mining, electricity generation, mechanised agriculture, and petroleum-powered vehicles-are all on the rise, with the most marked increases in rapidly developing and industrialising low-income and middle-income countries. Pollution mitigation and prevention can yield large net gains both for human health and the economy. ...air quality improvements in the high-income countries have not only reduced deaths from cardiovascular and respiratory disease but have also yielded substantial economic gains. Pollution control, in turn, will benefit from efforts to slow the pace of climate change (SDG 13) by transitioning to a sustainable, circular economy that relies on non-polluting renewable energy, on efficient industrial processes that produce little waste, and on transport systems that restrict use of private vehicles in cities, enhance public transport, and promote active travel.
Certain
strains residing in the human gut produce colibactin, a small-molecule genotoxin implicated in colorectal cancer pathogenesis. However, colibactin's chemical structure and the molecular ...mechanism underlying its genotoxic effects have remained unknown for more than a decade. Here we combine an untargeted DNA adductomics approach with chemical synthesis to identify and characterize a covalent DNA modification from human cell lines treated with colibactin-producing
Our data establish that colibactin alkylates DNA with an unusual electrophilic cyclopropane. We show that this metabolite is formed in mice colonized by colibactin-producing
and is likely derived from an initially formed, unstable colibactin-DNA adduct. Our findings reveal a potential biomarker for colibactin exposure and provide mechanistic insights into how a gut microbe may contribute to colorectal carcinogenesis.
ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer
. The majority of ARID1A mutations are inactivating mutations and lead to loss of ...ARID1A expression
, which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.
A target to suppress inflammation Samson, Leona D
Science (American Association for the Advancement of Science),
11/2018, Letnik:
362, Številka:
6416
Journal Article
Recenzirano
A small-molecule inhibitor of the OGG1 DNA glycosylase has anti-inflammatory effects
Tissues that are stressed by injury or by invading pathogens elicit signals for the recruitment of inflammatory ...immune cells such as macrophages and neutrophils, which consequently release reactive oxygen and nitrogen species (RONS) as part of the innate immune response (
1
). This flood of RONS is important for directly attacking invading pathogens and for warding off infection of damaged tissue. But the efficiency of RONS in inactivating invading cells and viruses creates an Achilles heel of the innate immune response, namely that RONS are also able to kill and mutate cells in healthy tissues. Although inflammatory responses are usually counterbalanced over time by an opposing anti-inflammatory response, achieving the optimal balance with minimal collateral tissue damage is difficult even in healthy individuals, and virtually impossible in individuals with certain disease conditions such as ulcerative colitis and rheumatoid arthritis (
2
). Therefore, the development of anti-inflammatory drugs, targeting inflammation from a variety of different angles, has flourished in recent decades. On page 834 of this issue, Visnes
et al.
(
3
) present an entirely new approach to suppressing the inflammatory response. Counter-intuitively, this approach involves the inhibition of the 8-oxoguanine DNA glycosylase 1 (OGG1) DNA repair enzyme that recognizes and initiates the base excision repair of 7,8-dihydro-8-oxoguanine (8-oxoG), one of the major types of DNA base damage induced by RONS.
The integrity of our DNA is challenged with at least 100,000 lesions per cell on a daily basis. Failure to repair DNA damage efficiently can lead to cancer, immunodeficiency, and neurodegenerative ...disease. Base excision repair (BER) recognizes and repairs minimally helix-distorting DNA base lesions induced by both endogenous and exogenous DNA damaging agents. Levels of BER-initiating DNA glycosylases can vary between individuals, suggesting that quantitating and understanding interindividual differences in DNA repair capacity (DRC) may enable us to predict and prevent disease in a personalized manner. However, population studies of BER capacity have been limited because most methods used to measure BER activity are cumbersome, time consuming and, for the most part, only allow for the analysis of one DNA glycosylase at a time. We have developed a fluorescence-based multiplex flow-cytometric host cell reactivation assay wherein the activity of several enzymes four BER-initiating DNA glycosylases and the downstream processing apurinic/apyrimidinic endonuclease 1 (APE1) can be tested simultaneously, at single-cell resolution, in vivo. Taking advantage of the transcriptional properties of several DNA lesions, we have engineered specific fluorescent reporter plasmids for quantitative measurements of 8-oxoguanine DNA glycosylase, alkyladenine DNA glycosylase, MutY DNA glycosylase, uracil DNA glycosylase, and APE1 activity. We have used these reporters to measure differences in BER capacity across a panel of cell lines collected from healthy individuals, and to generate mathematical models that predict cellular sensitivity to methylmethane sulfonate, H₂O₂, and 5-FU from DRC. Moreover, we demonstrate the suitability of these reporters to measure differences in DRC in multiple pathways using primary lymphocytes from two individuals.
Programmed necrosis has emerged as a crucial modulator of cell death in response to several forms of cellular stress. In one form of programmed necrotic cell death, induced by cytotoxic alkylating ...agents, hyperactivation of poly-ADP-ribose polymerase (PARP) leads to cellular NAD and ATP depletion, mitochondrial dysfunction, reactive oxygen species formation, and ensuing cell death. Here, we show that the protein encoded by the human AlkB homolog 7 (ALKBH7) gene plays a pivotal role in DNA-damaging agent-induced programmed necrosis by triggering the collapse of mitochondrial membrane potential and large-scale loss of mitochondrial function that lead to energy depletion and cellular demise. Depletion of ALKBH7 suppresses necrotic cell death induced by numerous alkylating and oxidizing agents while having no effect on apoptotic cell death. Like wild-type cells, ALKBH7-depleted cells undergo PARP hyperactivation and NAD depletion after severe DNA damage but, unlike wild-type cells, exhibit rapid recovery of intracellular NAD and ATP levels. Consistent with the recovery of cellular bioenergetics, ALKBH7-depleted cells maintain their mitochondrial membrane potential, plasma membrane integrity, and viability. Our results uncover a novel role for a mammalian AlkB homolog in programmed necrosis, presenting a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death.
The capacity to repair different types of DNA damage varies among individuals, making them more or less susceptible to the detrimental health consequences of damage exposures. Current methods for ...measuring DNA repair capacity (DRC) are relatively labor intensive, often indirect, and usually limited to a single repair pathway. Here, we describe a fluorescence-based multiplex flow-cytometric host cell reactivation assay (FM-HCR) that measures the ability of human cells to repair plasmid reporters, each bearing a different type of DNA damage or different doses of the same type of DNA damage. FM-HCR simultaneously measures repair capacity in any four of the following pathways: nucleotide excision repair, mismatch repair, base excision repair, nonhomologous end joining, homologous recombination, and methylguanine methyltransferase. We show that FM-HCR can measure interindividual DRC differences in a panel of 24 cell lines derived from genetically diverse, apparently healthy individuals, and we show that FM-HCR may be used to identify inhibitors or enhancers of DRC. We further develop a next-generation sequencing-based HCR assay (HCR-Seq) that detects rare transcriptional mutagenesis events due to lesion bypass by RNA polymerase, providing an added dimension to DRC measurements. FM-HCR and HCR-Seq provide powerful tools for exploring relationships among global DRC, disease susceptibility, and optimal treatment.
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