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    A novel DNA damage recognition protein in Schizosaccharomyces pombe.

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    Authors
    Pearson, Steven J
    Wharton, Stephen
    Watson, Amanda J
    Begum, Ghazala
    Butt, Amna
    Glynn, Nicola
    Williams, David M
    Shibata, Takayuki
    Santibanez-Koref, Mauro F
    Margison, Geoffrey P
    Affiliation
    Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
    Issue Date
    2006
    
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    Abstract
    Toxic and mutagenic O6-alkylguanine adducts in DNA are repaired by O6-alkylguanine-DNA alkyltransferases (MGMT) by transfer of the alkyl group to a cysteine residue in the active site. Comparisons in silico of prokaryotes and lower eukaryotes reveal the presence of a group of proteins [alkyltransferase-like (ATL) proteins] showing amino acid sequence similarity to MGMT, but where the cysteine at the putative active site is replaced by tryptophan. To examine whether ATL proteins play a role in the biological effects of alkylating agents, we inactivated the gene, referred to as atl1+, in Schizosaccharomyces pombe, an organism that does not possess a functional MGMT homologue. The mutants are substantially more susceptible to the toxic effects of the methylating agents, N-methyl-N-nitrosourea, N-methyl-N'nitro-N-nitrosoguanidine and methyl methanesulfonate and longer chain alkylating agents including N-ethyl-N-nitrosourea, ethyl methanesulfonate, N-propyl-N-nitrosourea and N-butyl-N-nitrosourea. Purified Atl1 protein does not transfer methyl groups from O6-methylguanine in [3H]-methylated DNA but reversibly inhibits methyl transfer by human MGMT. Atl1 binds to short single-stranded oligonucleotides containing O6-methyl, -benzyl, -4-bromothenyl or -hydroxyethyl-guanine but does not remove the alkyl group or base and does not cleave the oligonucleotide in the region of the lesion. This suggests that Atl1 acts by binding to O6-alkylguanine lesions and signalling them for processing by other DNA repair pathways. This is the first report describing an activity that protects S.pombe against the toxic effects of O6-alkylguanine adducts and the biological function of a family of proteins that is widely found in prokaryotes and lower eukaryotes.
    Citation
    A novel DNA damage recognition protein in Schizosaccharomyces pombe. 2006, 34 (8):2347-54 Nucleic Acids Res.
    Journal
    Nucleic Acids Research
    URI
    http://hdl.handle.net/10541/72794
    DOI
    10.1093/nar/gkl270
    PubMed ID
    16679453
    Type
    Article
    Language
    en
    ISSN
    1362-4962
    ae974a485f413a2113503eed53cd6c53
    10.1093/nar/gkl270
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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