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1. Development and Application of a Slot-Blot Assay Using the Damage Sensing Protein Atl1 to Detect and Quantify O 6 -Alkylated Guanine Bases in DNA.

Author

Yaakub, Hanum, Howell, Anthony, Margison, Geoffrey P., and Povey, Andrew C.

Subjects
DNA alkylation, HUMAN DNA, ALKYLATING agents, SCHIZOSACCHAROMYCES pombe, TEMOZOLOMIDE, METHYLGUANINE
Abstract

Humans are unavoidably exposed to numerous different mutagenic DNA alkylating agents (AAs), but their role in the initiation of cancers is uncertain, in part due to difficulties in assessing human exposure. To address this, we have developed a screening method that measures promutagenic O6-alkylguanines (O6-AlkGs) in DNA and applied it to human DNA samples. The method exploits the ability of the Schizosaccharomyces pombe alkyltransferase-like protein (Atl1) to recognise and bind to a wide range of O6-AlkGs in DNA. We established an Atl1-based slot-blot (ASB) assay and validated it using calf thymus DNA alkylated in vitro with a range of alkylating agents and both calf thymus and human placental DNA methylated in vitro with temozolomide (TMZ). ASB signals were directly proportional to the levels of O6-meG in these controls. Pre-treatment of DNA with the DNA repair protein O6-methylguanine–DNA methyltransferase (MGMT) reduced binding of Atl1, confirming its specificity. In addition, MCF 10A cells were treated with 500 μM TMZ and the extracted DNA, analysed using the ASB, was found to contain 1.34 fmoles O6 -meG/μg DNA. Of six human breast tumour DNA samples assessed, five had detectable O6-AlkG levels (mean ± SD 1.24 ± 0.25 O6-meG equivalents/μg DNA. This study shows the potential usefulness of the ASB assay to detect and quantify total O6-AlkGs in human DNA samples. [ABSTRACT FROM AUTHOR]

Published
2024
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5. The DNA Alkyltransferase Family of DNA Repair Proteins: Common Mechanisms, Diverse Functions.

Author

Tessmer, Ingrid and Margison, Geoffrey P.

Subjects
*DNA repair, *SPARE parts, *ALKYL group, *PROTEINS, *DNA
Abstract

DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O6-alkylguanine and O4-alkylthymine bases in DNA. Their mechanism involves binding to the damaged DNA and flipping the base out of the DNA helix into the active site pocket in the protein. Alkyltransferases then directly and irreversibly transfer the alkyl group from the base to the active site cysteine residue. In contrast, alkyltransferase-like proteins recruit nucleotide excision repair components for O6-alkylguanine elimination. One or more of these proteins are found in all kingdoms of life, and where this has been determined, their overall DNA repair mechanism is strictly conserved between organisms. Nevertheless, between species, subtle as well as more extensive differences that affect target lesion preferences and/or introduce additional protein functions have evolved. Examining these differences and their functional consequences is intricately entwined with understanding the details of their DNA repair mechanism(s) and their biological roles. In this review, we will present and discuss various aspects of the current status of knowledge on this intriguing protein family. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Mass Spectrometric Analysis of the Active Site Tryptic Peptide of Recombinant O6‑Methylguanine-DNA Methyltransferase Following Incubation with Human Colorectal DNA Reveals the Presence of an O6‑Alkylguanine Adductome.

Author

Abdelhady, Rasha, Senthong, Pattama, Eyers, Claire E., Reamtong, Onrapak, Cowley, Elizabeth, Cannizzaro, Luca, Stimpson, Joanna, Cain, Kathleen, Wilkinson, Oliver J., Williams, Nicholas H., Barran, Perdita E., Margison, Geoffrey P., Williams, David M., and Povey, Andrew C.

Published
2023
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9. QSAR and Chemical Read-Across Analysis of 370 Potential MGMT Inactivators to Identify the Structural Features Influencing Inactivation Potency.

Author

Sun, Guohui, Bai, Peiying, Fan, Tengjiao, Zhao, Lijiao, Zhong, Rugang, McElhinney, R. Stanley, McMurry, T. Brian H., Donnelly, Dorothy J., McCormick, Joan E., Kelly, Jane, and Margison, Geoffrey P.

Subjects
ANALYTICAL chemistry, O6-Methylguanine-DNA Methyltransferase, STRUCTURE-activity relationships, AMINO group, IONIZATION energy, VIRUS inactivation
Abstract

O6-methylguanine-DNA methyltransferase (MGMT) constitutes an important cellular mechanism for repairing potentially cytotoxic DNA damage induced by guanine O6-alkylating agents and can render cells highly resistant to certain cancer chemotherapeutic drugs. A wide variety of potential MGMT inactivators have been designed and synthesized for the purpose of overcoming MGMT-mediated tumor resistance. We determined the inactivation potency of these compounds against human recombinant MGMT using [3H]-methylated-DNA-based MGMT inactivation assays and calculated the IC50 values. Using the results of 370 compounds, we performed quantitative structure–activity relationship (QSAR) modeling to identify the correlation between the chemical structure and MGMT-inactivating ability. Modeling was based on subdividing the sorted pIC50 values or on chemical structures or was random. A total of nine molecular descriptors were presented in the model equation, in which the mechanistic interpretation indicated that the status of nitrogen atoms, aliphatic primary amino groups, the presence of O-S at topological distance 3, the presence of Al-O-Ar/Ar-O-Ar/R..O..R/R-O-C=X, the ionization potential and hydrogen bond donors are the main factors responsible for inactivation ability. The final model was of high internal robustness, goodness of fit and prediction ability (R2pr = 0.7474, Q2Fn = 0.7375–0.7437, CCCpr = 0.8530). After the best splitting model was decided, we established the full model based on the entire set of compounds using the same descriptor combination. We also used a similarity-based read-across technique to further improve the external predictive ability of the model (R2pr = 0.7528, Q2Fn = 0.7387–0.7449, CCCpr = 0.8560). The prediction quality of 66 true external compounds was checked using the "Prediction Reliability Indicator" tool. In summary, we defined key structural features associated with MGMT inactivation, thus allowing for the design of MGMT inactivators that might improve clinical outcomes in cancer treatment. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Alkyltransferase-like proteins

Author

Margison, Geoffrey P., Butt, Amna, Pearson, Steven J., Wharton, Stephen, Watson, Amanda J., Marriott, Andrew, Caetano, Cátia M.P.F., Hollins, Jeffrey J., Rukazenkova, Natalia, Begum, Ghazala, and Santibáñez-Koref, Mauro F.

Published
2007
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30. Alkylpurine–DNA–N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients

Author

Agnihotri, Sameer, Gajadhar, Aaron S., Ternamian, Christian, Gorlia, Thierry, Diefes, Kristin L., Mischel, Paul S., Kelly, Joanna, McGown, Gail, Thorncroft, Mary, Carlson, Brett L., Sarkaria, Jann N., Margison, Geoffrey P., Aldape, Kenneth, Hawkins, Cynthia, Hegi, Monika, and Guha, Abhijit

Published
2012
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31. Flipping of alkylated DNA damage bridges base and nucleotide excision repair

Author

Tubbs, Julie L., Latypov, Vitaly, Kanugula, Sreenivas, Butt, Amna, Melikishvili, Manana, Kraehenbuehl, Rolf, Fleck, Oliver, Marriott, Andrew, Watson, Amanda J., Verbeek, Barbara, McGown, Gail, Thorncroft, Mary, Santibanez-Koref, Mauro F., Millington, Christopher, Arvai, Andrew S., Kroeger, Matthew D., Peterson, Lisa A., Williams, David M., Fried, Michael G., Margison, Geoffrey P., Pegg, Anthony E., and Tainer, John A.

Published
2009
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