N1-methyl A (1meA)

FULL NAME: N1-methyladenine


DESCRIPTION:
N1-methyladenine (1MeA) is formed by alkylating agents mainly in single-stranded DNA and has been detected in vitro and in vivo. 1MeA is cytotoxic because it disturbs DNA replication. 1-Methyldeoxyadenosine is known to be unstable due to a base-catalyzed Dimroth rearrangement, a complex mechanism, the net result of which is the migration of the N1 methyl group to the exocyclic N6 position of adenine. A specialized DNA repair system protects cells from N1-substituted DNA lesions. The AlkB enzyme of the adaptive response repairs 1MeA both in vitro and in vivo in an oxidative reaction that liberates formaldehyde from the methylated base, affording complete reversal of the damage. The role of AlkB in the repair of 1MeA seems to be the prevention of genotoxicity, because this very toxic adduct is only weakly mutagenic in cells. Studies of 1MeA in vivo reveal that the lesion severely blocks DNA replication, but the replication block can be partially overcome by the induction of SOS bypass polymerases. The 1MeA blockade is completely removed in AlkB-proficient cells, underscoring the physiological relevance of the AlkB system for countering the toxicity of this base. While very toxic, as indicated above, 1MeA is at best weakly mutagenic. To the extent that it is mutagenic, 1MeA induces A to T mutations, which are enhanced following induction of the SOS polymerases.

DAMAGE TYPE: methylation damage


DNA DAMAGE SOURCE(S) (MAIN):
SN2 methylating agents
methyl methanesulfonate (MMS)
methyl chloride
methyl bromide
methyl iodide
alkylating agents


DNA DAMAGE EFFECT(S) (MAIN):
A→T transversion
cytotoxic
stalled replication fork


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


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


DNA repair protein(s) related to damage:
ALKBH3
AlkB
ALKBH2
ANPG (MPG)


Last modification date: Oct. 8, 2011