Repair of alkylated DNA: recent advances.
Cytotoxic and mutagenic methylated bases in DNA can be generated by endogenous and environmental alkylating agents. Such damaged bases are removed by three distinct strategies. The abundant toxic lesion 3-methyladenine (3-alkyladenine) is excised by a specific DNA glycosylase that initiates a base excision-repair process. The toxic lesions 1-methyladenine and 3-methylcytosine are corrected by oxidative DNA demethylation catalyzed by DNA dioxygenases. These enzymes release the methyl moiety as formaldehyde, directly reversing the base damage. The third strategy involves the mutagenic and cytotoxic lesion O(6)-methylguanine which is also repaired by direct reversal but uses a different mechanism. Here, the methyl group is transferred from the lesion to a specific cysteine residue within the methyltransferase itself. In this review, we briefly describe endogenous alkylating agents and the extensively investigated DNA repair enzymes, mammalian 3-methyladenine-DNA glycosylase and O(6)-methylguanine-DNA methyltransferase. We provide a more detailed description of the structures and biochemical properties of the recently discovered DNA dioxygenases.
Sedgwick
Barbara
B
Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK. Barbara.Sedgwick@cancer.org.uk
Bates
Paul A
PA
Paik
Johanna
J
Jacobs
Susan C
SC
Lindahl
Tomas
T
D000477:Alkylating Agents / Q000737:chemistry / Q000378:metabolism*; D000478:Alkylation; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D019175:DNA Methylation; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000378:metabolism*
D000477:Alkylating Agents; D012436:S-Adenosylmethionine; D004247:DNA; D045643:DNA Repair Enzymes