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Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation-π interactions.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2012 Nov 13; Vol. 109 (46), pp. 18755-60. Date of Electronic Publication: 2012 Oct 29. - Publication Year :
- 2012
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 109
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 23112169
- Full Text :
- https://doi.org/10.1073/pnas.1209451109