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Nucleic Acids Research 2006 34(8):2347-2354; doi:10.1093/nar/gkl270
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Published online 5 May 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Article

A novel DNA damage recognition protein in Schizosaccharomyces pombe

Steven J. Pearson, Stephen Wharton, Amanda J. Watson, Ghazala Begum, Amna Butt, Nicola Glynn, David M. Williams1, Takayuki Shibata1, Mauro F. Santibáñez-Koref2 and Geoffrey P. Margison*

Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester Manchester, UK 1 Centre for Chemical Biology, Department of Chemistry, University of Sheffield UK 2 Institute of Human Genetics, University of Newcastle-upon-Tyne UK

*To whom correspondence should be addressed. Tel: +44 161 446 3183; Fax: +44 161 446 8306; Email: gmargison{at}picr.man.ac.uk

Received March 3, 2006. Revised March 29, 2006. Accepted April 1, 2006.

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.


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An O6-methylguanine-DNA Methyltransferase-like Protein from Thermus thermophilus Interacts with a Nucleotide Excision Repair Protein
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[Abstract] [Full Text] [PDF]


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