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Your search keyword '"Thorncroft, Mary"' showing total 3 results
Start Over Author "Thorncroft, Mary" Topic guanine
3 results on '"Thorncroft, Mary"'

1. Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation-π interactions.

Author

Wilkinson OJ, Latypov V, Tubbs JL, Millington CL, Morita R, Blackburn H, Marriott A, McGown G, Thorncroft M, Watson AJ, Connolly BA, Grasby JA, Masui R, Hunter CA, Tainer JA, Margison GP, and Williams DM

Subjects
Alkyl and Aryl Transferases genetics, Alkyl and Aryl Transferases metabolism, Alkylation, Amino Acid Substitution, Bacterial Proteins chemistry, Bacterial Proteins genetics, Bacterial Proteins metabolism, Crystallography, X-Ray, Guanine metabolism, Mutation, Missense, Oligodeoxyribonucleotides genetics, Oligodeoxyribonucleotides metabolism, Protein Binding, Protein Structure, Tertiary, Schizosaccharomyces genetics, Schizosaccharomyces pombe Proteins genetics, Schizosaccharomyces pombe Proteins metabolism, Thermus thermophilus enzymology, Alkyl and Aryl Transferases chemistry, DNA Repair physiology, Guanine chemistry, Oligodeoxyribonucleotides chemistry, Schizosaccharomyces enzymology, Schizosaccharomyces pombe Proteins chemistry
Abstract

Alkyltransferase-like (ATL) proteins in Schizosaccharomyces pombe (Atl1) and Thermus thermophilus (TTHA1564) protect against the adverse effects of DNA alkylation damage by flagging O(6)-alkylguanine lesions for nucleotide excision repair (NER). We show that both ATL proteins bind with high affinity to oligodeoxyribonucleotides containing O(6)-alkylguanines differing in size, polarity, and charge of the alkyl group. However, Atl1 shows a greater ability than TTHA1564 to distinguish between O(6)-alkylguanine and guanine and in an unprecedented mechanism uses Arg69 to probe the electrostatic potential surface of O(6)-alkylguanine, as determined using molecular mechanics calculations. An unexpected consequence of this feature is the recognition of 2,6-diaminopurine and 2-aminopurine, as confirmed in crystal structures of respective Atl1-DNA complexes. O(6)-Alkylguanine and guanine discrimination is diminished for Atl1 R69A and R69F mutants, and S. pombe R69A and R69F mutants are more sensitive toward alkylating agent toxicity, revealing the key role of Arg69 in identifying O(6)-alkylguanines critical for NER recognition.

Published
2012
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2. Atl1 regulates choice between global genome and transcription-coupled repair of O(6)-alkylguanines.

Author

Latypov VF, Tubbs JL, Watson AJ, Marriott AS, McGown G, Thorncroft M, Wilkinson OJ, Senthong P, Butt A, Arvai AS, Millington CL, Povey AC, Williams DM, Santibanez-Koref MF, Tainer JA, and Margison GP

Subjects
Alkyl and Aryl Transferases chemistry, Alkyl and Aryl Transferases genetics, Blotting, Western, Crystallography, X-Ray, DNA Damage, DNA, Fungal chemistry, DNA, Fungal genetics, DNA, Fungal metabolism, Flow Cytometry, G1 Phase drug effects, Genome, Fungal genetics, Guanine chemistry, Guanine metabolism, Methylnitronitrosoguanidine toxicity, Models, Molecular, Mutation, Nitrosourea Compounds toxicity, Nucleic Acid Conformation, Protein Binding, Protein Structure, Tertiary, Schizosaccharomyces drug effects, Schizosaccharomyces genetics, Schizosaccharomyces metabolism, Schizosaccharomyces pombe Proteins chemistry, Schizosaccharomyces pombe Proteins genetics, Transcription, Genetic genetics, Alkyl and Aryl Transferases metabolism, DNA Repair, Guanine analogs & derivatives, Schizosaccharomyces pombe Proteins metabolism
Abstract

Nucleotide excision repair (NER) has long been known to remove DNA lesions induced by chemical carcinogens, and the molecular mechanism has been partially elucidated. Here we demonstrate that in Schizosaccharomyces pombe a DNA recognition protein, alkyltransferase-like 1 (Atl1), can play a pivotal role in selecting a specific NER pathway, depending on the nature of the DNA modification. The relative ease of dissociation of Atl1 from DNA containing small O(6)-alkylguanines allows accurate completion of global genome repair (GGR), whereas strong Atl1 binding to bulky O(6)-alkylguanines blocks GGR, stalls the transcription machinery, and diverts the damage to transcription-coupled repair. Our findings redraw the initial stages of the NER process in those organisms that express an alkyltransferase-like gene and raise the question of whether or not O(6)-alkylguanine lesions that are poor substrates for the alkyltransferase proteins in higher eukaryotes might, by analogy, signal such lesions for repair by NER., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Published
2012
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3. Alkylated DNA damage flipping 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.

Subjects
Models, Molecular, Alkyl and Aryl Transferases, Binding Sites, Guanine, Alkylation, DNA Repair, Protein Conformation, DNA, Crystallography, X-Ray, Article, parasitic diseases, Humans, DNA Damage, Protein Binding
Abstract

Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O(6)-alkylguanine-DNA alkyltransferase (AGT) and paradoxically protect cells from the biological effects of DNA alkylation damage, despite lacking the reactive cysteine and alkyltransferase activity of AGT. Here we determine Schizosaccharomyces pombe ATL structures without and with damaged DNA containing the endogenous lesion O(6)-methylguanine or cigarette-smoke-derived O(6)-4-(3-pyridyl)-4-oxobutylguanine. These results reveal non-enzymatic DNA nucleotide flipping plus increased DNA distortion and binding pocket size compared to AGT. Our analysis of lesion-binding site conservation identifies new ATLs in sea anemone and ancestral archaea, indicating that ATL interactions are ancestral to present-day repair pathways in all domains of life. Genetic connections to mammalian XPG (also known as ERCC5) and ERCC1 in S. pombe homologues Rad13 and Swi10 and biochemical interactions with Escherichia coli UvrA and UvrC combined with structural results reveal that ATLs sculpt alkylated DNA to create a genetic and structural intersection of base damage processing with nucleotide excision repair.

Published
2009

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