Abstract
The genome of living cells is continuously exposed to endogenous and exogenous attacks, and this is particularly amplified at high temperatures. Alkylating agents cause DNA damage, leading to mutations and cell death; for this reason, they also play a central role in chemotherapy treatments. A class of enzymes known as AGTs (alkylguanine-DNA-alkyltransferases) protects the DNA from mutations caused by alkylating agents, in particular in the recognition and repair of alkylated guanines in O6-position. The peculiar irreversible self-alkylation reaction of these enzymes triggered numerous studies, especially on the human homologue, in order to identify effective inhibitors in the fight against cancer. In modern biotechnology, engineered variants of AGTs are developed to be used as protein tags for the attachment of chemical ligands. In the last decade, research on AGTs from (hyper)thermophilic sources proved useful as a model system to clarify numerous phenomena, also common for mesophilic enzymes. This review traces recent progress in this class of thermozymes, emphasizing their usefulness in basic research and their consequent advantages for in vivo and in vitro biotechnological applications.
Highlights
Monofunctional alkylating agents, a class of mutagenic and carcinogenic agents present in the environment, induce DNA alkylation in several positions including guanine at O6 (O6-MG; 6% of adducts formed), the N7 of guanine (N7-MG; 70%), and the N3 of adenine (N3-MA; 9%) [1]
A class of enzymes known as AGTs protects the DNA from mutations caused by alkylating agents, in particular in the recognition and repair of alkylated guanines in O6-position
It was proposed that the toxic effect occurs after DNA replication, because the O6-AG incorrectly base-pairs with thymine generating a transition from G:C to A:T [2]
Summary
Monofunctional alkylating agents, a class of mutagenic and carcinogenic agents present in the environment, induce DNA alkylation in several positions including guanine at O6 (O6-MG; 6% of adducts formed), the N7 of guanine (N7-MG; 70%), and the N3 of adenine (N3-MA; 9%) [1]. Apart from conventional DNA repair pathways as Mismatch Excision Repair (MMR), Nucleotide Excision Repair (NER), Base Excision Repair (BER), alkylated-DNA protein alkyl-transferases (called O6-alkyl-guanine-DNA-alkyl-transferase (AGT or OGT) or O6-methyl-guanine- DNA-alkyl-transferase (MGMT); EC: 2.1.1.63) perform the direct repair of alkylation damage in DNA [3,4]. They represent the major factor in counteracting the effects of alkylating agents that form such adducts [4]. The disadvantage of this elegant catalysis is that, upon alkylation, the protein is self-inactivated and destabilized, triggering its recognition by cellular systems to be degraded by the proteasome [8,9]
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