Spotlight pubs.acs.org/crt
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ARISTOLOCHIC ACID MUTATIONAL SIGNATURE REVEALED For thousands of years, Aristolochia herbs have been used in traditional medicine to induce weight loss and relieve menstrual symptoms and rheumatism. Aristolochic acid (AA), a nitrophenanthrene carboxylic acid found in Aristolochia plants, was identified as the causative agent in Balkan endemic nephropathy and epidemiologically linked to the high incidence of upper urinary tract urothelial cell carcinoma (UTUC) in patients treated with Aristolochia remedies. AA nephrotoxicity and carcinogenicity is attributed to the formation of AA-DNA adducts in the kidneys and ureters. Early studies demonstrated that AA adducts predominantly induce A to T transversion mutations, especially in TP53, the gene encoding the tumor suppressor protein p53. However, it was unknown whether other genes were also susceptible to AA adduct formation or whether AA adducts could be linked to other forms of cancer besides UTUC. In recently reported bids to answer these questions, two research groups independently evaluated the genome-wide mutational signature of AA exposure in UTUC patients. Song Ling Poon et al. ((2013) Sci. Transl. Med., 5, 197ra101) and Margaret L. Hoang et al. ((2013) Sci. Transl. Med., 5, 197ra102) each identified the consensus sequence for AA mutation and noted that transversions occurred primarily on nontranscribed DNA strands, with a high occurrence in genes involved in chromatin remodeling and at splice acceptor sites (both targets that may contribute to AA carcinogenesis). Furthermore, Poon et al. detected AA-like mutational patterns in 11 out of 93 screened cases of hepatocellular carcinoma, while Hoang et al. used the mutational pattern to implicate AA exposure in one UTUC case that had previously been attributed to smoking. Such results support the use of mutational signatures to pinpoint previous exposure to particular carcinogens, a potentially powerful approach for performing molecular epidemiology studies. Heidi A. Dahlmann
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NEW INHIBITORS OF TRANSLESION DNA SYNTHESIS POLYMERASES
selectivity against hpolη with second-generation ITBA derivatives. Heidi A. Dahlmann
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Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and depletion of dopamine in the brain. While late onset PD has been associated with exposure to environmental toxicants such as pesticides and metals, early onset PD has been linked to genetic causes, including mutations in thePARK7 gene. DJ-1, the multifunctional protein encoded by PARK7, was known to mediate cellular dopamine reuptake, act as an intracellular antioxidant, and interact with the antioxidant enzyme Cu/Zn superoxide dismutase 1 in a copper ion concentration-dependent manner. Thus, Benny Björkblom, Simon Møller, and co-workers hypothesized that DJ-1 itself directly interacted with metals and that loss of function in clinically relevant DJ-1 mutants (such as DJ-1A104T or D149A) could contribute to PD etiology ((2013) J. Biol. Chem., 288, 22809−22820). The research team demonstrated that wild-type (wt) recombinant human DJ-1 (and to varying extents, PD DJ-1 mutants) could bind Cu(I), Cu(II), and mercury ions. Furthermore, mouse embryonic fibroblasts (MEFs) expressing wtDJ-I appeared to be protected from copper- and mercuryinduced toxicity but not when expressing DJ-1A104T or D149A. Intriguingly, in MEFs treated with dopamine in combination with metal ions the protective effect of wtDJ-1 was reduced, apparently due to increased oxidative stress in the cells. The authors note that the dopamine-induced increased sensitivity to metal toxicity may explain why dopaminergic neurons are a main target for degeneration in PD. Heidi A. Dahlmann
Adapted from Coggins et al. (2013) ACS Chem. Biol., 8, 1722− 1729. Copyright 2013 American Chemical Society.
A leading form of anticancer treatment involves damaging DNA to create lesions that force DNA polymerases to stall during replication, triggering apoptosis. However, this intended process can be thwarted by polymerases (pols) that are capable of replicating past damaged DNA in the process of translesion synthesis (TLS). For example, Y-family pols, especially human pol eta (hpolη), are notorious for bypassing DNA lesions induced by anticancer drugs (like doxorubicin and cisplatin) in an error-prone manner. Mutations generated during TLS may allow the tumor to evolve further drug-resistance mechanisms. An attractive means to thwart this vicious cycle would be the administration of TLS-pol inhibitors in conjunction with conventional DNA-damaging agents. A research team led by Robert L. Eoff has now identified indolethiobarbiuric acid (ITBA) derivates, which are structurally related to N-benzoyl indolylbarbituric acids that are known to possess anticancer activity, as inhibitors of TLSpols, including hpolη ((2013) ACS Chem. Biol., 8, 1722−1729). Kinetics experiments indicated that the ITBA derivatives act as allosteric or partial inhibitors of hpolη activity, an observation supported by molecular docking analyses. The ITBA derivatives displayed antihpolη IC50 values down to 16 μM, meaning that they are not as potent as previously reported hpolη inhibitors; however, the authors hope to improve the potency and © 2013 American Chemical Society
PARKINSON PROTEIN PROTECTS AGAINST METAL-INDUCED CYTOTOXICITY
Published: October 21, 2013 1419
dx.doi.org/10.1021/tx400339f | Chem. Res. Toxicol. 2013, 26, 1419−1420
Chemical Research in Toxicology
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Spotlight
SELENIUM VS SULFUR: RESISTANCE TO ENZYME OXIDATION
network mediated by the host cell surface receptor c-Met. Ultimately, the research team determined that SIRT2 activity was critical for facilitating late-stage infection (likely the process of bacterial replication) of L. monocytogenes in vitro and in mice. Further studies are needed to identify exactly which of the genes deregulated by L. monocytogenes-induced histone deacetylation plays a role in enhancing the infectivity of the pathogen. Heidi A. Dahlmann
Adapted from Snider et al. (2013) Biochemistry, 52, 5472−5481. Copyright 2013 American Chemical Society.
In nature, enzymes utilizing catalytically active thiols (found in cysteine, Cys) vastly outnumber those using selenols (found in selenocysteine, Sec). At first, this seems unsurprising since selenols oxidize much more readily than thiols, which renders Sec-bearing enzymes theoretically more susceptible to inactivation. Paradoxically, certain enzymes containing Secresidues in aerobic organisms are more resistant to oxidative inactivation than their Cys-bearing homologues. For example, this phenomenon occurs in thioredoxin reductase (TR) enzymes, as recently reported by Robert J. Hondal and co-workers ((2013) Biochemistry, 52, 5472−5481). In this study, the resistance of three TR enzymes (Cyscontaining Drosphila melanogaster- derived TR (DmTR), Seccontaining mouse mitochondrial TR, and DmTR engineered to contain Sec) to oxidative inactivation were compared. The Sec-containing enzymes consistently maintained higher activity levels than DmTR upon exposure to biologically relevant oxidants such as hydrogen peroxide, hydroxyl radical, peroxynitrite, or reactive halogen species. This phenomenon was attributed to the “Janus-faced” nature of selenium: while a selenolate is highly nucleophilic, allowing for it to be easily oxidized, the resulting Se-oxide is highly electrophilic, allowing for rapid reduction back to the selenolate form. Meanwhile, thiols and thiolates are more prone to overoxidation because oxides of sulfur are less electrophilic in comparison. Heidi A. Dahlmann
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BACTERIAL PATHOGEN INFLUENCES HOST CELL TRANSCRIPTION Listeria monocytogenes, a foodborne pathogen that can cause disease in immunocompromised or pregnant hosts, expresses proteins that enable host cell invasion, proliferation, and immune system evasion. A growing awareness of the influence of bacterial pathogens on host cell chromatin (condensed structure of DNA wrapped around histone proteins within the eukaryotic nucleus) has launched investigations of how pathogens such as L. monocytogenes control host cell transcription by mediating histone modifications. One such study, recently reported by a team led by Pascale Cossart and Mélanie A. Hamon, revealed that L. monocytogenes internalin B (InlB, a bacterial cell-surface protein previously known to promote entry into host cells) induces deacetylation of lysine 18 on the histone protein H3 (H3K18) ((2013) Science, DOI: 10.1126/science.1238858). As a result of this process, L. monocytogenes is capable of altering the transcription of hundreds of host cell genes. During the course of their study, the research team identified host cell human sirtuin 2 (SIRT2) as the protein that deacetylates H3K18. InlB was found to induce SIRT2 translocation from the cytoplasm to the nucleus via the activation of a signaling 1420
dx.doi.org/10.1021/tx400339f | Chem. Res. Toxicol. 2013, 26, 1419−1420
