alkylating agents


DESCRIPTION: Alkylating agents can react with 12 different positions of DNA bases, including all exocyclic oxygens and most of ring nitrogens, and can also modify oxygen atoms in the phosphates groups of the sugar-phosphate backbone. Depending on the mode of action, alkylating agents are divided into two types: SN1-type agents (e.g. N-methyl-N-nitrosourea, MNU) alkylate both oxygens and nitrogens in nucleic acids, and SN2-type agents (e.g. methyl methanesulfonate, MMS) alkylate mainly nitrogens. In general, ring nitrogen atoms engaged in hydrogen bonding are almost non-reactive in double-stranded DNA (dsDNA), but can be more readily alkylated in single stranded DNA (ssDNA) or RNA (e.g. N3 of cytosine and N1 of adenine) (reviewed by (Drablos et al., 2004;Sedgwick, 2004) Nieminuszczy & Grzesiuk, 2007).

The major product of DNA base methylation is N7-methylguanine, a rather non-mutagenic and non replication-blocking lesion. However, destabilization of the N-glycosidic bond due to the N7-substitution of guanine results in the formation of AP-sites or imidazole ring opening to yield very mutagenic lesion 7me-FapyG (Tudek et al., 1992). The second most common DNA base methylation is N3-methyladenine (3-meA), which is a potent replication-blocking lesion and is perhaps the most toxic adduct produced by alkylating agents, resulting in TP53 induction, S-phase arrest, chromosomal aberrations and apoptosis (Engelward et al., 1998). In contrast to the limited miscoding potential of N-purines, O6-methylguanine (O6-meG) and, to a lesser extent, O4-methylthymine (O4-meT) are major contributors to mutagenicity induced by alkylating agents. Endogenous agents may alkylate DNA bases, and among them the best known is S-adenosyl-L methionine (SAM) (Rydberg & Lindahl, 1982).

Alkylating agents inhibit cell division by reacting with DNA and are used as antineoplastic agents.

DNA DAMAGES:
O6-ethyl G (O6etG)
1-OH-propyl A (1hpA)
N3-methyl T (3meT)
O2-methyl T (O2meT)
3-methyl C (3meC)
O2-methyl C (O2meC)
MePT
O4-methyl T (O4meT)
3-methylC (3meC) in RNA
N3-methyl G (3meG)
1-ethyl A (1etA)
1-propyl A (1pA)
3-methyl A (3meA)
3-ethyl C (3etC)
3-propyl C (3pC)
O6-methyl G (O6meG)
Fapy-7meG from Fapy-7meG:C
N3-methylT (3meT) in ssDNA
N7-methyl G (7meG)
1-methyl G (1meG)
N1-methyl A (1meA)
7-methyl A (7meA)
3-methyl A (3-meA) in ssDNA
3-methylC (3meC) in ssDNA


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NAME STRUCTURE PROTEINS DNA DAMAGE EFFECT(S) PATHWAY(S) RELATED
O6-ethyl G (O6etG) MGMT cytotoxic direct reversal (DR)
1-OH-propyl A (1hpA) mutagenesis
point mutation
N3-methyl T (3meT) FTO
AlkB
cytotoxic
mutagenesis
point mutation
stalled replication fork
substitution
T→A transversion
transversion
direct reversal (DR)
O2-methyl T (O2meT) AlkA cytotoxic base excision repair (BER)
3-methyl C (3meC) AlkB
ALKBH2
ALKBH3
ANPG (MPG)
cytotoxic
stalled replication fork
base excision repair (BER)
direct reversal (DR)
O2-methyl C (O2meC) AlkA cytotoxic base excision repair (BER)
MePT Ada cytotoxic
stalled replication fork
direct reversal (DR)
O4-methyl T (O4meT) Ogt
Ada
MGMT
cytotoxic
mutagenesis
point mutation
substitution
T→C transition
transition
direct reversal (DR)
3-methylC (3meC) in RNA AlkB mutagenesis direct reversal (DR)
N3-methyl G (3meG) AlkA
Tag
ANPG (MPG)
cytotoxic
stalled replication fork
base excision repair (BER)
1-ethyl A (1etA) ALKBH2
AlkB
ALKBH3
cytotoxic
stalled replication fork
direct reversal (DR)
1-propyl A (1pA) mutagenesis
point mutation
3-methyl A (3meA) AlkA
Tag
ANPG (MPG)
AP-site
A→T transversion
cell cycle arrest
cytotoxic
mutagenesis
point mutation
stalled replication fork
base excision repair (BER)
3-ethyl C (3etC) AlkB C→T transition
cytotoxic
mutagenesis
point mutation
stalled replication fork
substitution
transition
direct reversal (DR)
3-propyl C (3pC) mutagenesis
point mutation
O6-methyl G (O6meG) Ada
Ogt
MGMT
G→A transition
mutagenesis
point mutation
substitution
transition
direct reversal (DR)
Fapy-7meG from Fapy-7meG:C hOGG1 mutagenesis
point mutation
stalled replication fork
substitution
base excision repair (BER)
N3-methylT (3meT) in ssDNA FTO
AlkB
cell cycle arrest
mutagenesis
point mutation
stalled replication fork
substitution
T→A transversion
transversion
direct reversal (DR)
N7-methyl G (7meG) AlkA
Fpg (MutM)
Tag
ANPG (MPG)
no mutagenesis base excision repair (BER)
1-methyl G (1meG) AlkB
ANPG (MPG)
G→A transition
G→T transversion
mutagenesis
point mutation
substitution
transition
transversion
base excision repair (BER)
direct reversal (DR)
N1-methyl A (1meA) ALKBH3
AlkB
ALKBH2
ANPG (MPG)
A→T transversion
cytotoxic
stalled replication fork
base excision repair (BER)
direct reversal (DR)
7-methyl A (7meA) AlkA
ANPG (MPG)
A→G transition
mutagenesis
point mutation
substitution
transition
base excision repair (BER)
3-methyl A (3-meA) in ssDNA AlkA AP-site
A→T transversion
cell cycle arrest
cytotoxic
mutagenesis
point mutation
stalled replication fork
transversion
base excision repair (BER)
3-methylC (3meC) in ssDNA ALKBH3
ALKBH1
AlkB
mutagenesis direct reversal (DR)

Last modification date: Aug. 14, 2011