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Article ; Online: The DNA Alkyltransferase Family of DNA Repair Proteins: Common Mechanisms, Diverse Functions.

Tessmer, Ingrid / Margison, Geoffrey P

International journal of molecular sciences

2023 Volume 25, Issue 1

Abstract: DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic ... ...

Abstract	DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O
MeSH term(s)	Alkyl and Aryl Transferases ; Cysteine ; DNA Repair ; DNA
Chemical Substances	DNA alkyltransferase (EC 2.5.1.-) ; Alkyl and Aryl Transferases (EC 2.5.-) ; Cysteine (K848JZ4886) ; DNA (9007-49-2)
Language	English
Publishing date	2023-12-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25010463
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Article ; Online: The DNA Alkyltransferase Family of DNA Repair Proteins

Ingrid Tessmer / Geoffrey P. Margison

International Journal of Molecular Sciences, Vol 25, Iss 1, p

Common Mechanisms, Diverse Functions

2023 Volume 463

Abstract: DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O 6 -alkylguanine and O 4 -alkylthymine bases in DNA. Their mechanism involves binding to the damaged DNA and flipping the ... ...

Abstract	DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O 6 -alkylguanine and O 4 -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 O 6 -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.
Keywords	DNA repair ; O6-alkylguanine-DNA alkyltransferase ; alkylation damage ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	612
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article: QSAR and Chemical Read-Across Analysis of 370 Potential MGMT Inactivators to Identify the Structural Features Influencing Inactivation Potency.

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 / Margison, Geoffrey P

Pharmaceutics

2023 Volume 15, Issue 8

Abstract: ... ...

Abstract	O
Language	English
Publishing date	2023-08-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15082170
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Article ; Online: Mass Spectrometric Analysis of the Active Site Tryptic Peptide of Recombinant

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 / Povey, Andrew C

Chemical research in toxicology

2023 Volume 36, Issue 12, Page(s) 1921–1929

Abstract: Human exposure to DNA alkylating agents is poorly characterized, partly because only a limited range of specific alkyl DNA adducts have been quantified. The human DNA repair protein, ...

Abstract	Human exposure to DNA alkylating agents is poorly characterized, partly because only a limited range of specific alkyl DNA adducts have been quantified. The human DNA repair protein,
MeSH term(s)	Humans ; Catalytic Domain ; Colorectal Neoplasms ; Cysteine ; DNA/chemistry ; DNA Repair ; Mass Spectrometry ; O(6)-Methylguanine-DNA Methyltransferase/genetics ; Oligodeoxyribonucleotides/chemistry ; Peptides
Chemical Substances	Cysteine (K848JZ4886) ; DNA (9007-49-2) ; mecysteine (RQ6L463N3B) ; O(6)-Methylguanine-DNA Methyltransferase (EC 2.1.1.63) ; Oligodeoxyribonucleotides ; Peptides ; S-methylcysteine (A34I1H07YM) ; MGMT protein, human (EC 2.1.1.63)
Language	English
Publishing date	2023-11-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.3c00207
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Article ; Online: Synthesis of oligodeoxyribonucleotides containing a tricyclic thio analogue of

Abdu, Kabir / Aiertza, Miren K / Wilkinson, Oliver J / Senthong, Pattama / Craggs, Timothy D / Povey, Andrew C / Margison, Geoffrey P / Williams, David M

Nucleosides, nucleotides & nucleic acids

2020 Volume 39, Issue 8, Page(s) 1108–1121

Abstract: ... ...

Abstract	Promutagenic
MeSH term(s)	Alkyl and Aryl Transferases/chemistry ; Alkyl and Aryl Transferases/metabolism ; Guanine/analogs & derivatives ; Guanine/chemistry ; Guanine/metabolism ; Humans ; Models, Molecular ; Molecular Structure ; O(6)-Methylguanine-DNA Methyltransferase/chemistry ; O(6)-Methylguanine-DNA Methyltransferase/metabolism ; Oligodeoxyribonucleotides/chemical synthesis ; Oligodeoxyribonucleotides/chemistry ; Oligodeoxyribonucleotides/metabolism ; Sulfhydryl Compounds/chemistry ; Sulfhydryl Compounds/metabolism
Chemical Substances	Oligodeoxyribonucleotides ; Sulfhydryl Compounds ; Guanine (5Z93L87A1R) ; O-(6)-methylguanine (9B710FV2AE) ; O(6)-Methylguanine-DNA Methyltransferase (EC 2.1.1.63) ; ATL1 protein, S pombe (EC 2.5.-) ; Alkyl and Aryl Transferases (EC 2.5.-)
Language	English
Publishing date	2020-05-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2008956-9
ISSN	1532-2335 ; 1525-7770
ISSN (online)	1532-2335
ISSN	1525-7770
DOI	10.1080/15257770.2020.1764971
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Article ; Online: O

Ezerskyte, Monika / Paredes, João A / Malvezzi, Stefano / Burns, John A / Margison, Geoffrey P / Olsson, Magnus / Scicchitano, David A / Dreij, Kristian

Proceedings of the National Academy of Sciences of the United States of America

2018 Volume 115, Issue 18, Page(s) 4731–4736

Abstract: Altered protein function due to mutagenesis plays an important role in disease development. This is perhaps most evident in tumorigenesis and the associated loss or gain of function of tumor-suppressor genes and oncogenes. The extent to which lesion- ... ...

Abstract	Altered protein function due to mutagenesis plays an important role in disease development. This is perhaps most evident in tumorigenesis and the associated loss or gain of function of tumor-suppressor genes and oncogenes. The extent to which lesion-induced transcriptional mutagenesis (TM) influences protein function and its contribution to the development of disease is not well understood. In this study, the impact of
MeSH term(s)	Amino Acid Substitution ; Apoptosis/genetics ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; DNA Repair ; G1 Phase Cell Cycle Checkpoints/genetics ; Guanine/analogs & derivatives ; Guanine/metabolism ; Humans ; Mutagenesis ; Mutation, Missense ; S Phase Cell Cycle Checkpoints/genetics ; Transcription, Genetic ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	TP53 protein, human ; Tumor Suppressor Protein p53 ; Guanine (5Z93L87A1R) ; O-(6)-methylguanine (9B710FV2AE)
Language	English
Publishing date	2018-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1721764115
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Zs.A 1148: Show issues

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Article ; Online: Targeting O⁶-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy.

Kaina, Bernd / Margison, Geoffrey P / Christmann, Markus

Cellular and molecular life sciences : CMLS

2010 Volume 67, Issue 21, Page(s) 3663–3681

Abstract: O (6)-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O (6)-methylguanine and O (6)-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are ... ...

Abstract	O (6)-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O (6)-methylguanine and O (6)-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic, and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued. A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O (6)-benzylguanine and O (6)-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise for enhancing the effectiveness of alkylating agent chemotherapy.
MeSH term(s)	Animals ; Antineoplastic Agents, Alkylating/pharmacology ; Antineoplastic Agents, Alkylating/therapeutic use ; Clinical Trials as Topic ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Humans ; Neoplasms/drug therapy ; Neoplasms/enzymology ; O(6)-Methylguanine-DNA Methyltransferase/antagonists & inhibitors ; O(6)-Methylguanine-DNA Methyltransferase/metabolism
Chemical Substances	Antineoplastic Agents, Alkylating ; Enzyme Inhibitors ; O(6)-Methylguanine-DNA Methyltransferase (EC 2.1.1.63)
Language	English
Publishing date	2010-08-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-010-0491-7
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Article ; Online: Differential chemosensitivity to antifolate drugs between RAS and BRAF melanoma cells.

Arozarena, Imanol / Goicoechea, Ibai / Erice, Oihane / Ferguson, Jennnifer / Margison, Geoffrey P / Wellbrock, Claudia

Molecular cancer

2014 Volume 13, Page(s) 154

Abstract: Background: The importance of the genetic background of cancer cells for the individual susceptibility to cancer treatments is increasingly apparent. In melanoma, the existence of a BRAF mutation is a main predictor for successful BRAF-targeted therapy. ...

Abstract	Background: The importance of the genetic background of cancer cells for the individual susceptibility to cancer treatments is increasingly apparent. In melanoma, the existence of a BRAF mutation is a main predictor for successful BRAF-targeted therapy. However, despite initial successes with these therapies, patients relapse within a year and have to move on to other therapies. Moreover, patients harbouring a wild type BRAF gene (including 25% with NRAS mutations) still require alternative treatment such as chemotherapy. Multiple genetic parameters have been associated with response to chemotherapy, but despite their high frequency in melanoma nothing is known about the impact of BRAF or NRAS mutations on the response to chemotherapeutic agents. Methods: Using cell proliferation and DNA methylation assays, FACS analysis and quantitative-RT-PCR we have characterised the response of a panel of NRAS and BRAF mutant melanoma cell lines to various chemotherapy drugs, amongst them dacarbazine (DTIC) and temozolomide (TMZ) and DNA synthesis inhibitors. Results: Although both, DTIC and TMZ act as alkylating agents through the same intermediate, NRAS and BRAF mutant cells responded differentially only to DTIC. Further analysis revealed that the growth-inhibitory effects mediated by DTIC were rather due to interference with nucleotide salvaging, and that NRAS mutant melanoma cells exhibit higher activity of the nucleotide synthesis enzymes IMPDH and TK1. Importantly, the enhanced ability of RAS mutant cells to use nucleotide salvaging resulted in resistance to DHFR inhibitors. Conclusion: In summary, our data suggest that the genetic background in melanoma cells influences the response to inhibitors blocking de novo DNA synthesis, and that defining the RAS mutation status could be used to stratify patients for the use of antifolate drugs.
MeSH term(s)	Antineoplastic Agents/administration & dosage ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA/biosynthesis ; DNA/genetics ; DNA Methylation/genetics ; Dacarbazine/administration & dosage ; Dacarbazine/analogs & derivatives ; Enzyme Inhibitors/administration & dosage ; GTP Phosphohydrolases/genetics ; Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/pathology ; Membrane Proteins/genetics ; Mutation ; Proto-Oncogene Proteins B-raf/genetics ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Temozolomide
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; Membrane Proteins ; Dacarbazine (7GR28W0FJI) ; DNA (9007-49-2) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; NRAS protein, human (EC 3.6.1.-) ; Temozolomide (YF1K15M17Y)
Language	English
Publishing date	2014-06-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2091373-4
ISSN	1476-4598 ; 1476-4598
ISSN (online)	1476-4598
ISSN	1476-4598
DOI	10.1186/1476-4598-13-154
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Article: Improvement of chemotherapy efficacy by inactivation of a DNA-repair pathway.

Middleton, Mark R / Margison, Geoffrey P

The Lancet. Oncology

2003 Volume 4, Issue 1, Page(s) 37–44

Abstract: Tumour resistance and dose-limiting toxic effects restrict treatment with most chemotherapeutic drugs. Elucidation of the mechanisms of these effects could permit the development of ways to improve the effectiveness of currently used agents until better ... ...

Abstract	Tumour resistance and dose-limiting toxic effects restrict treatment with most chemotherapeutic drugs. Elucidation of the mechanisms of these effects could permit the development of ways to improve the effectiveness of currently used agents until better therapeutic agents are developed. Several types of alkylating agents are used in the treatment of cancer. The DNA repair protein, O6-alkylguanine-DNA alkyltransferase (ATase) is an important cellular resistance mechanism to one class of alkylating agents. This enzyme removes potentially lethal damage from DNA and experiments in vitro and in vivo have shown that its inactivation can reverse resistance to such agents. Clinical trials of drugs that inactivate ATase are underway and early results indicate that they are active in tumour tissues. However, the ATase present in normal tissues, particularly bone marrow, is also inactivated, necessitating a reduction in the dose of alkylating agent. An important question is whether, in the absence of any tumour-specific delivery strategy, such drugs will improve therapeutic effectiveness; initial reports are not promising.
MeSH term(s)	Animals ; Antineoplastic Agents, Alkylating/administration & dosage ; Antineoplastic Agents, Alkylating/chemistry ; Antineoplastic Agents, Alkylating/pharmacology ; DNA Damage ; DNA Repair/drug effects ; DNA Repair/physiology ; Drug Resistance, Neoplasm/physiology ; Humans ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Nucleotidyltransferases/chemistry ; Nucleotidyltransferases/drug effects ; Nucleotidyltransferases/metabolism ; O(6)-Methylguanine-DNA Methyltransferase/metabolism
Chemical Substances	Antineoplastic Agents, Alkylating ; O(6)-Methylguanine-DNA Methyltransferase (EC 2.1.1.63) ; Nucleotidyltransferases (EC 2.7.7.-) ; glutamine-synthetase adenylyltransferase (EC 2.7.7.42)
Language	English
Publishing date	2003-04-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2049730-1
ISSN	1474-5488 ; 1470-2045
ISSN (online)	1474-5488
ISSN	1470-2045
DOI	10.1016/s1470-2045(03)00959-8
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Zs.A 5696: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Expression of O-Alkylguanine-DNA Alkyltransferase in Normal and Malignant Bladder Tissue of Egyptian Patients.

Saad, Abir A / Kassem, Heba Sh / Povey, Andrew C / Margison, Geoffrey P

Journal of nucleic acids

2010 Volume 2010, Page(s) 840230

Abstract: ... in tumour (P < .01) based on protein. There was no effect of gender or bilharzia infection status. IF showed ... were significantly higher than those in uninvolved tissues (42.8 ± 13.5% P = .04) and (1.89 ± 1.42; P ...

Abstract	Bladder tumour tissues and corresponding uninvolved mucosa (normal tissue) of Egyptian bladder cancer patients were assessed for O(6)-alkylguanine-DNA-alkyltransferase (MGMT) activity by functional assay of tissue extracts (36 paired samples), and distribution by immunofluorescence (IF) microscopy of fixed material (24 paired samples). MGMT varied widely from 42-253 fmoles/mg protein and from 3.2-40 fmoles/μg DNA in normal and 58-468 fmoles/mg protein and 2.5-49.5 fmoles/mg protein, in the tumour tissues; only one tumour had undetectable activity. Pairwise comparison of MGMT activity in tumour and adjacent normal tissue showed no significant difference based on DNA content but was 1.75-fold higher in tumour (P < .01) based on protein. There was no effect of gender or bilharzia infection status. IF showed that in tumours, both the mean percentage of positive nuclei (57.3 ± 20.3%) and mean integrated IF (5.47 ± 3.66) were significantly higher than those in uninvolved tissues (42.8 ± 13.5% P = .04) and (1.89 ± 1.42; P < .01), respectively. These observations suggest that, overall, MGMT levels are increased during human bladder carcinogenesis and that MGMT downregulation is not a common feature of bladder cancers. Based on this, bladder cancers would be expected to be relatively resistant to chemotherapy which involved O(6)-guanine alkylating antitumour agents.
Language	English
Publishing date	2010-10-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2549000-X
ISSN	2090-021X ; 2090-021X
ISSN (online)	2090-021X
ISSN	2090-021X
DOI	10.4061/2010/840230
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