Alkyltransferase-like proteins.
Recent in silico analysis has revealed the presence of a group of proteins in pro and lower eukaryotes, but not in Man, that show extensive amino acid sequence similarity to known O(6)-alkylguanine-DNA alkyltransferases, but where the cysteine at the putative active site is replaced by another residue, usually tryptophan. Here we review recent work on these proteins, which we designate as alkyltransferase-like (ATL) proteins, and consider their mechanism of action and role in protecting the host organisms against the biological effects of O(6)-alkylating agents, and their evolution. ATL proteins from Escherichia coli (eAtl, transcribed from the ybaz open reading frame) and Schizosaccharomyces pombe (Atl1) are able to bind to a range of O(6)-alkylguanine residues in DNA and to reversibly inhibit the action of the human alkyltransferase (MGMT) upon these substrates. Isolated proteins were not able to remove the methyl group in O(6)-methylguanine-containing DNA or oligonucleotides, neither did they display glycosylase or endonuclease activity. S. pombe does not contain a functional alkyltransferase and atl1 inactivation sensitises this organism to a variety of alkylating agents, suggesting that Atl1 acts by binding to O(6)-alkylguanine lesions and signalling them for processing by other DNA repair pathways. Currently we cannot exclude the possibility that ATL proteins arose through independent mutation of the alkyltransferase gene in different organisms. However, analyses of the proteins from E. coli and S. pombe, are consistent with a common function.
Margison
Geoffrey P
GP
Cancer Research-UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom. gmargison@picr.man.ac.uk
Butt
Amna
A
Pearson
Steven J
SJ
Wharton
Stephen
S
Watson
Amanda J
AJ
Marriott
Andrew
A
Caetano
Cátia M P F
CM
Hollins
Jeffrey J
JJ
Rukazenkova
Natalia
N
Begum
Ghazala
G
Santibáñez-Koref
Mauro F
MF
D019883:Alkyl and Aryl Transferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000477:Alkylating Agents / Q000633:toxicity; D000595:Amino Acid Sequence; D000818:Animals; D015254:DNA Modification Methylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D017353:Gene Deletion; D005800:Genes, Fungal; D006801:Humans; D008969:Molecular Sequence Data; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D000477:Alkylating Agents; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D019853:O(6)-Methylguanine-DNA Methyltransferase; C510506:ATL1 protein, S pombe; D019883:Alkyl and Aryl Transferases; D045643:DNA Repair Enzymes