N3-methylT (3meT) in ssDNA

FULL NAME: 3-methylthymine in ssDNA


DESCRIPTION:
N3-methylthymine (3MeT, 3meT) has been found both in vitro and in vivo and is formed through the reaction of DNA with SN2 alkylating agents such as MMS. This adduct is a very weak substrate for AlkB, and it is a strong block to replication in vivo, which can be only slightly overcome by SOS bypass polymerase induction. Recently, fat mass obesity associated protein (FTO) has been shown as a 2-oxoglutarate-dependent demethylase for nucleic acid. FTO can efficiently repair 3MeT in single-stranded DNA but not in double-stranded DNA; it also shows strong activity on the demethylation of 3-methyluracil in single-stranded RNA. While there are numerous epidemiological studies associating the FTO gene with obesity, the biological basis for metabolic effects of this gene are still under investigation. From the standpoint of its potential to induce genetic change, 3MeT is 60% mutagenic in SOS−/AlkB− cells, providing mostly T → A (47%) and T → C (9%) mutations. Studies performed in vitro also show that 3MeT is a strong block to the Klenow fragment of DNA polymerase I, which slightly increases deoxythymidine triphosphate (dTTP) incorporation on a poly(dC-d3MeT) template; interestingly, T is exclusively incorporated opposite the analogous 3-ethyldeoxythymidine adduct in one study, whereas A is exclusively incorporated in another.

DAMAGE TYPE: methylation damage


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


DNA DAMAGE EFFECT(S) (MAIN):
cell cycle arrest
mutagenesis
point mutation
stalled replication fork
substitution
T→A transversion
transversion


DNA DAMAGE EFFECT(S) (MINOR):
mutagenesis
point mutation
substitution
T→C transition
transition


PATHWAYS:
direct reversal (DR)


DNA repair protein(s) related to damage:
FTO
AlkB


Last modification date: Aug. 30, 2011