1,N6-etheno-A (1εA)

FULL NAME: 1,N6-ethenoadenine


DESCRIPTION:
1,N(6)-Ethenoadenine (epsilonA, εA) is an exocyclic DNA adduct introduced to DNA by vinyl chloride and related compounds as well as in the consequence of oxidative stress and unsaturated lipid peroxidation (LPO). This highly genotoxic DNA damage is chemically unstable and either depurinates or converts into pyrimidine ring-opened secondary lesions. This bifunctional DNA lesion arises endogenously under normal physiological conditions in both rodents and humans. Of great toxicological concern is the observation that eA is induced by common industrial agent vinyl chloride and its metabolites, such as chloroacetaldehyde. eA also occurs in chronically inflamed human and rodent tissues. Oxidative stress associated with inflammation is increasingly being linked to neurological disease, cancer promotion and accelerated aging. In duplex DNA, eA can be repaired in vitro by glycosylases of the BER pathway. Mammalian cells can also repair etheno lesions by this route in vivo. Indeed, the BER enzyme AAG and its homologs are likely to be the primary vehicles of repair of eA in the duplex genomes of eukaryotes. In contrast, the in vivo repair of etheno adducts in E.coli was not clearly understood until recently; for example, one early study showed that neither BER nor NER figures prominently in etheno lesion repair. Early genetic studies on the mutagenicity of eA in E.coli reinforced this conundrum. The eA adduct was neither toxic nor mutagenic despite the fact that the base lacks any structural possibility of Watson–Crick complementarity. The issues raised in these studies were resolved in 2005 when biochemical studies provided the possibility that the direct reversal enzyme, AlkB, may play a significant role in the defense of cells against this type of bifunctional DNA damage. These biochemical studies showed that AlkB and its human homolog ABH3 can efficiently repair eA in vitro. AlkB uses a unique iron-mediated biochemical reaction involving α-ketoglutarate as a cofactor to putatively epoxidize the exocyclic double bond of eA. An epoxide may be hydrolyzed to a glycol with the glycol moiety being liberated as the dialdehyde, glyoxal. The direct reversal mechanism is also likely to be operative in vivo, as evidenced by genetic studies in which a single-stranded vector containing a single eA was replicated in AlkB-proficient and -deficient E.coli cells. In AlkB-deficient cells, eA is 35% mutagenic, yielding 25% A → T, 5% A → G and 5% A → C mutations. SOS induction causes an increased incorporation of dAMP opposite to eA.

DAMAGE TYPE: DNA adduct


DNA DAMAGE SOURCE(S) (MAIN):
chloroethylene oxide
lipid peroxidation (LPO)
vinyl chloride metabolites
chloroacetaldehyde (CAA)


DNA DAMAGE SOURCE(S) (MINOR):
ethylene oxide (EtO)


DNA DAMAGE EFFECT(S) (MAIN):
A→T transversion
mutagenesis
point mutation
transversion


DNA DAMAGE EFFECT(S) (MINOR):
A→C transversion
A→G transition
DNA backbone distortion
mutagenesis
point mutation
stalled replication fork
transition
transversion


PATHWAYS:
base excision repair (BER)
direct reversal (DR)


DNA repair protein(s) related to damage:
AlkA
Fpg (MutM)
ANPG (MPG)
AlkB
ALKBH2


Last modification date: Oct. 12, 2011