Maureen McKeague

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McKeague

First Name

Maureen

ORCID

0000-0002-3750-6027

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Publications 1 - 9 of 9

Quantification and Mapping of Alkylation in the Human Genome Reveal Single Nucleotide Resolution Precursors of Mutational Signatures
Jiang, Yang; Mingard, Cécile; Huber, Sabrina M.; et al. (2023)
ACS Central Science
Chemical modifications to DNA bases, including DNA adducts arising from reactions with electrophilic chemicals, are well-known to impact cell growth, miscode during replication, and influence disease etiology. However, knowledge of how genomic sequences and structures influence the accumulation of alkylated DNA bases is not broadly characterized with high resolution, nor have these patterns been linked with overall quantities of modified bases in the genome. For benzo(a) pyrene (BaP), a ubiquitous environmental carcinogen, we developed a single-nucleotide resolution damage sequencing method to map in a human lung cell line the main mutagenic adduct arising from BaP. Furthermore, we combined this analysis with quantitative mass spectrometry to evaluate the dose-response profile of adduct formation. By comparing damage abundance with DNase hypersensitive sites, transcription levels, and other genome annotation data, we found that although overall adduct levels rose with increasing chemical exposure concentration, genomic distribution patterns consistently correlated with chromatin state and transcriptional status. Moreover, due to the single nucleotide resolution characteristics of this DNA damage map, we could determine preferred DNA triad sequence contexts for alkylation accumulation, revealing a characteristic DNA damage signature. This new BaP damage signature had a profile highly similar to mutational signatures identified previously in lung cancer genomes from smokers. Thus, these data provide insight on how genomic features shape the accumulation of alkylation products in the genome and predictive strategies for linking single-nucleotide resolution in vitro damage maps with human cancer mutations.
Green Toxicology: Connecting Green Chemistry and Modern Toxicology
Krebs, Johanna; McKeague, Maureen (2020)
Chemical Research in Toxicology
A major thrust in the concept of green chemistry is to eliminate the production of hazardous materials. Thus, sustainable toxicity testing is required for its successful implementation. Here, we present the principles of green toxicology, a concept less well known than green chemistry, but indispensable for the sustainable development of chemical products. Green toxicology entails early testing through non-animal methods, such as novel in vitro and in silico technologies in toxicity prediction, to obtain benign products in benign processes with reduced exposure. The future of non-testing toxicity prediction entails both an improved creation, management, and use of big data to optimize chemical space coverage and an increased mechanistic and biological pathway understanding which can be integrated in prediction tools. This perspective provides an introduction to chemists and toxicologists to the combined idea of green toxicology, rather than providing a comprehensive overview. Specifically, we (1) provide a brief overview of recently emerging technologies, (2) highlight the importance of collaboration between researchers to implement and integrate green toxicology in the chemical industry, and (3) present challenges that come along with the emerging technologies and propose possibilities for their better application and wider use in the future.
Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide
Kubitschek, Jasmina; Takhaveev, Vakil; Mingard, Cécile; et al. (2025)
Nucleic Acids Research
Temozolomide kills cancer cells by forming O⁶-methylguanine (O⁶-MeG), which leads to cell cycle arrest and apoptosis. However, O⁶-MeG repair by O⁶-methylguanine-DNA methyltransferase (MGMT) contributes to drug resistance. Characterizing genomic profiles of O⁶-MeG could elucidate how O⁶-MeG accumulation is influenced by repair, but there are no methods to map genomic locations of O⁶-MeG. Here, we developed an immunoprecipitation- and polymerase-stalling-based method, termed O⁶-MeG-seq, to locate O⁶-MeG across the whole genome at single-nucleotide resolution. We analyzed O⁶-MeG formation and repair across sequence contexts and functional genomic regions in relation to MGMT expression in a glioblastoma-derived cell line. O⁶-MeG signatures were highly similar to mutational signatures from patients previously treated with temozolomide. Furthermore, MGMT did not preferentially repair O⁶-MeG with respect to sequence context, chromatin state or gene expression level, however, may protect oncogenes from mutations. Finally, we found an MGMT-independent strand bias in O⁶-MeG accumulation in highly expressed genes. These data provide high resolution insight on how O⁶-MeG formation and repair are impacted by genome structure and nucleotide sequence. Further, O⁶-MeG-seq is expected to enable future studies of DNA modification signatures as diagnostic markers for addressing drug resistance and preventing secondary cancers.
The Base Pairing Partner Modulates Alkylguanine Alkyltransferase
McKeague, Maureen; Otto, Claudia; Räz, Michael H.; et al. (2018)
ACS Chemical Biology
Nucleotide-Resolution Genome-Wide Mapping of Oxidative DNA Damage by Click-Code-Seq
Wu, Junzhou; McKeague, Maureen; Sturla, Shana J. (2018)
Journal of the American Chemical Society
Dietary modulation of mitochondrial DNA damage: implications in aging and associated diseases
Lam, Juwela; McKeague, Maureen (2019)
Journal of Nutritional Biochemistry
Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O^6-methylguanine in vivo
Kraus, Alexander; McKeague, Maureen; Seiwert, Nina; et al. (2019)
Archives of Toxicology
Next-generation DNA damage sequencing
Mingard, Cécile; Wu, Junzhou; McKeague, Maureen; et al. (2020)
Chemical Society Reviews
Cellular DNA is constantly chemically altered by exogenous and endogenous agents. As all processes of life depend on the transmission of the genetic information, multiple biological processes exist to ensure genome integrity. Chemically damaged DNA has been linked to cancer and aging, therefore it is of great interest to map DNA damage formation and repair to elucidate the distribution of damage on a genome-wide scale. While the low abundance and inability to enzymatically amplify DNA damage are obstacles to genome-wide sequencing, new developments in the last few years have enabled high-resolution mapping of damaged bases. Recently, a number of DNA damage sequencing library construction strategies coupled to new data analysis pipelines allowed the mapping of specific DNA damage formation and repair at high and single nucleotide resolution. Strikingly, these advancements revealed that the distribution of DNA damage is heavily influenced by chromatin states and the binding of transcription factors. In the last seven years, these novel approaches have revealed new genomic maps of DNA damage distribution in a variety of organisms as generated by diverse chemical and physical DNA insults; oxidative stress, chemotherapeutic drugs, environmental pollutants, and sun exposure. Preferred sequences for damage formation and repair have been elucidated, thus making it possible to identify persistent weak spots in the genome as locations predicted to be vulnerable for mutation. As such, sequencing DNA damage will have an immense impact on our ability to elucidate mechanisms of disease initiation, and to evaluate and predict the efficacy of chemotherapeutic drugs.
Fluorescent Nucleobase Analogues with Extended Pi Surfaces Stabilize DNA Duplexes Containing O6‐Alkylguanine Adducts
Dahlmann, Heidi A.; Berger, Florence D.; Kung, Ryan W.; et al. (2018)
Helvetica Chimica Acta

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Maureen McKeague

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