Alkylation damage in DNA and RNA--repair mechanisms and medical significance.
Alkylation lesions in DNA and RNA result from endogenous compounds, environmental agents and alkylating drugs. Simple methylating agents, e.g. methylnitrosourea, tobacco-specific nitrosamines and drugs like temozolomide or streptozotocin, form adducts at N- and O-atoms in DNA bases. These lesions are mainly repaired by direct base repair, base excision repair, and to some extent by nucleotide excision repair (NER). The identified carcinogenicity of O(6)-methylguanine (O(6)-meG) is largely caused by its miscoding properties. Mutations from this lesion are prevented by O(6)-alkylG-DNA alkyltransferase (MGMT or AGT) that repairs the base in one step. However, the genotoxicity and cytotoxicity of O(6)-meG is mainly due to recognition of O(6)-meG/T (or C) mispairs by the mismatch repair system (MMR) and induction of futile repair cycles, eventually resulting in cytotoxic double-strand breaks. Therefore, inactivation of the MMR system in an AGT-defective background causes resistance to the killing effects of O(6)-alkylating agents, but not to the mutagenic effect. Bifunctional alkylating agents, such as chlorambucil or carmustine (BCNU), are commonly used anti-cancer drugs. DNA lesions caused by these agents are complex and require complex repair mechanisms. Thus, primary chloroethyl adducts at O(6)-G are repaired by AGT, while the secondary highly cytotoxic interstrand cross-links (ICLs) require nucleotide excision repair factors (e.g. XPF-ERCC1) for incision and homologous recombination to complete repair. Recently, Escherichia coli protein AlkB and human homologues were shown to be oxidative demethylases that repair cytotoxic 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) residues. Numerous AlkB homologues are found in viruses, bacteria and eukaryotes, including eight human homologues (hABH1-8). These have distinct locations in subcellular compartments and their functions are only starting to become understood. Surprisingly, AlkB and hABH3 also repair RNA. An evaluation of the biological effects of environmental mutagens, as well as understanding the mechanism of action and resistance to alkylating drugs require a detailed understanding of DNA repair processes.
Drabløs
Finn
F
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.
Feyzi
Emadoldin
E
Aas
Per Arne
PA
Vaagbø
Cathrine B
CB
Kavli
Bodil
B
Bratlie
Marit S
MS
Peña-Diaz
Javier
J
Otterlei
Marit
M
Slupphaug
Geir
G
Krokan
Hans E
HE
D000071498:AlkB Homolog 1, Histone H2a Dioxygenase; D000477:Alkylating Agents / Q000378:metabolism / Q000633:toxicity; D000478:Alkylation; D000595:Amino Acid Sequence; D000818:Animals; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010802:Phylogeny; D012313:RNA / Q000737:chemistry* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D000477:Alkylating Agents; D002273:Carcinogens; D029968:Escherichia coli Proteins; D012313:RNA; D004247:DNA; D006899:Mixed Function Oxygenases; C466427:AlkB protein, E coli; C499236:ALKBH1 protein, human; D000071498:AlkB Homolog 1, Histone H2a Dioxygenase; D045643:DNA Repair Enzymes