Table of Contents
What does O6-Methylguanine do?
O6-Methylguanine methyltransferase (MGMT) is a dealkylating enzyme that removes methyl groups from the O6 position of guanine, inducing resistance to alkylating chemotherapeutic agents [7].
What does O6-Methylguanine pair with?
The alkylated base O6-methylguanine (Fig. 1(c)) is mutagenic because it can pair with either thymine or cytosine during DNA synthesis.
What causes O6-Methylguanine?
Formation. 6-O-Methylguanine is formed in DNA by alkylation of the oxygen atom of guanine, most often by N-nitroso compounds (NOC) and sometimes due to methylation by other compounds such as endogenous S-adenosyl methionine.
Why is O6-Methylguanine mutagenic?
O6-methyl-guanine (O6MeG) is mutagenic because polymerases frequently misinsert T opposite O6MeG instead of C, both in vivo (9, 10) and in vitro (11–13).
What is methylation of guanine?
Guanine methylation is a ubiquitous process affecting DNA and various RNA species. N-7 guanine methylation (7-MG), though relatively less studied, could have a significant role in normal transcriptional regulation as well as in the onset and development of pathological conditions.
What is MGMT glioblastoma?
The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy.
What is methylated glioblastoma?
Glioblastoma multiforme (GBM) is a malignant brain tumor with poor prognosis. It accounts for 48.3% of malignant brain and central nervous system tumors in the USA [1].
What is MGMT repair?
O6-methylguanine-DNA methyltransferase, known as MGMT, is a DNA “suicide” repair enzyme. It repairs damaged guanine nucleotides by transferring the methyl at O6 site of guanine to its cysteine residues, thus avoiding gene mutation, cell death and tumorigenesis caused by alkylating agents.
What mutation is caused by alkylation of guanine at O6?
Alkylation of guanine at the O6 atom is a highly mutagenic DNA lesion because it alters the coding specificity of the base causing G:C to A:T transversion mutations.
Why is guanine methylated?
Guanine residues in DNA can become methylated when exposed to alkylating agents that are either ingested in the diet or administered as antineoplastic drugs (Fig. 15-15). The methyl group on the guanine ring causes it to mispair with thymine rather than to pair with cytosine, causing a point mutation.
What is MGMT in glioblastoma?
The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy.
Which enzyme removes the methyl group from O6-Methylguanine restoring the base to guanine?
Which anticancer drug is act by alkylation of DNA?
Cisplatin, oxaliplatin, carboplatin, chlorambucil, cyclophosphamide, mechlorethamine, and melphalan are some of the most important alkylating agents used for chemotherapy. The exposure of cells to alkylating agents causes a specific reduction in DNA synthesis, chromosomal aberrations, and genetic mutations [15].