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Cooperative cluster formation, DNA bending and base-flipping by O\(^6\)-alkylguanine-DNA alkyltransferase

Please always quote using this URN: urn:nbn:de:bvb:20-opus-133949
  • O\(^6\)-Alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O\(^6\)-alkylguanine and O\(^4\)-alkylthymine adducts in DNA, protecting the genome and also contributing to the resistance of tumors to chemotherapeutic alkylating agents. AGT binds DNA cooperatively, and cooperative interactions are likely to be important in lesion search and repair. We examined morphologies of complexes on long, unmodified DNAs, using analytical ultracentrifugation and atomic force microscopy. AGT formed clusters of 11 proteins. Longer clusters, predicted byO\(^6\)-Alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O\(^6\)-alkylguanine and O\(^4\)-alkylthymine adducts in DNA, protecting the genome and also contributing to the resistance of tumors to chemotherapeutic alkylating agents. AGT binds DNA cooperatively, and cooperative interactions are likely to be important in lesion search and repair. We examined morphologies of complexes on long, unmodified DNAs, using analytical ultracentrifugation and atomic force microscopy. AGT formed clusters of 11 proteins. Longer clusters, predicted by the McGhee-von Hippel model, were not seen even at high [protein]. Interestingly, torsional stress due to DNA unwinding has the potential to limit cluster size to the observed range. DNA at cluster sites showed bend angles (similar to 0, similar to 30 and similar to 60 degrees) that are consistent with models in which each protein induces a bend of similar to 30 degrees. Distributions of complexes along the DNA are incompatible with sequence specificity but suggest modest preference for DNA ends. These properties tell us about environments in which AGT may function. Small cooperative clusters and the ability to accommodate a range of DNA bends allow function where DNA topology is constrained, such as near DNA-replication complexes. The low sequence specificity allows efficient and unbiased lesion search across the entire genome.show moreshow less

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Metadaten
Author: Ingrid Tessmer, Manana Melikishvili, Michael G. Fried
URN:urn:nbn:de:bvb:20-opus-133949
Document Type:Journal article
Faculties:Fakultät für Biologie / Rudolf-Virchow-Zentrum
Language:English
Parent Title (English):Nucleic Acids Research
Year of Completion:2012
Volume:40
Issue:17
Pagenumber:8296-8308
Source:Nucleic Acids Research, 2012, Vol. 40, No. 17, 8296–8308. doi:10.1093/nar/gks574
DOI:https://doi.org/10.1093/nar/gks574
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:AGT; atomic-force microscopy; chemotherapy; complex stability; inactivation; noncooperative binding; nucleotide excision-repair; protein; restricition enzymes; stranded DNAs
Release Date:2017/02/21
Licence (German):License LogoCC BY-NC: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell