DNA damage can be directly reversed by dealkylation (Mitra and Kaina 1993). Three enzymes play a major role in reparative DNA dealkylation: MGMT, ALKBH2 and ALKBH3. MGMT dealkylates O-6-methylguanine in a suicidal reaction that inactivates the enzyme (Daniels et al. 2000, Rasimas et al. 2004, Duguid et al. 2005, Tubbs et al. 2007), while ALKBH2 and ALKBH3 dealkylate 1-methyladenine, 3-methyladenine, 3-methylcytosine and 1-ethyladenine (Duncan et al. 2002, Dango et al. 2011).
View original pathway at Reactome.
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Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, Carlsson LM, Kiess W, Vatin V, Lecoeur C, Delplanque J, Vaillant E, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, Le Stunff C, Bougnères P, Kovacs P, Marre M, Balkau B, Cauchi S, Chèvre JC, Froguel P.; ''Variation in FTO contributes to childhood obesity and severe adult obesity.''; PubMedEurope PMCScholia
Chen B, Liu H, Sun X, Yang CG.; ''Mechanistic insight into the recognition of single-stranded and double-stranded DNA substrates by ABH2 and ABH3.''; PubMedEurope PMCScholia
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Tubbs JL, Pegg AE, Tainer JA.; ''DNA binding, nucleotide flipping, and the helix-turn-helix motif in base repair by O6-alkylguanine-DNA alkyltransferase and its implications for cancer chemotherapy.''; PubMedEurope PMCScholia
Lindahl T, Demple B, Robins P.; ''Suicide inactivation of the E. coli O6-methylguanine-DNA methyltransferase.''; PubMedEurope PMCScholia
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ALKBH2 catalyzes the removal of the methyl group from 1-methyladenine (1-meA) in a reaction that depends on oxygen, alpha-ketoglutarate and Fe2+. ALKBH2 thus directly reverses alkylation damage of DNA in the form of 1-meA, releasing formaldehyde. ALKBH2 is ~4-fold more active on dsDNA containing 1-methyladenine than 3-methylcytosine (Duncan et al. 2002).
ALKBH2 catalyzes removal of the methyl group from 3-methylcytosine (3-meC) in a reaction that depends on oxygen, alpha-ketoglutarate and Fe2+. ALKBH2 thus directly reverses alkylation damage of DNA in the form of 3-meC, releasing formaldehyde (Duncan et al. 2002).
ALKBH2 catalyzes removal of the ethyl group from 1-ethyladenine (1-etA) in a reaction that depends on oxygen, alpha-ketoglutarate and Fe2+. ALKBH2 thus directly reverses alkylation damage of DNA in the form of 1-etA, releasing acetaldehyde (Duncan et al. 2002).
ALKBH3, a homolog of E.coli AlkB (Trewick et al. 2002), removes the methyl group from 1-methyladenine (1-meA) in a reaction dependent on alpha-ketoglutarate, oxygen and Fe2+. ALKBH3 directly reverses alkylating damage of DNA in the form of 1-meA that is accompanied with the release of formaldehyde (Duncan et al. 2002). The reversal of alkylating damage of dsDNA by ALKBH3 requires the presence of DNA helicase ASCC3, a component of the activating signal co-integrator complex (Dango et al. 2011). ALKBH3 can also repair methylated RNA (Aas et al. 2003).
ALKBH3, a homolog of E.coli AlkB (Trewick et al. 2002), removes the methyl group from 3-methylcytosine (3-meC) in a reaction dependent on alpha-ketoglutarate, oxygen and Fe2+. ALKBH3 directly reverses the alkylating damage of DNA in the form of 3-meC, releasing formaldehyde (Duncan et al. 2002). The reversal of alkylating damage of dsDNA by ALKBH3 requires the presence of DNA helicase ASCC3, a component of the activating signal co-integrator complex (Dango et al. 2011). ALKBH3 can also repair methylated RNA (Aas et al. 2003).
ALKBH3, a homolog of E.coli AlkB (Trewick et al. 2002), removes the ethyl group from 1-ethyladenine (1-etA) in a reaction dependent on alpha-ketoglutarate, oxygen and Fe2+. ALKBH3 directly reverses alkylating damage of DNA in the form of 1-etA, releasing acetaldehyde (Duncan et al. 2002). The reversal of alkylating damage of dsDNA by ALKBH3 requires the presence of DNA helicase ASCC3, a component of the activating signal co-activator complex (Dango et al. 2011). ALKBH3 can also repair methylated RNA (Aas et al. 2003).
ALKBH3 (ABH3) has a preference for binding single strand DNA or RNA containing alkylation damage. ALKBH3 associates with dsDNA containing 3-methylcytosine (3-meC-dsDNA) alkylation damage in the presence of ASCC3 DNA helicase. ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator complex, which unwinds dsDNA, providing an appropriate substrate for ALKBH3 (Duncan et al. 2002, Sundheim et al. 2006, Chen et al. 2010, Dango et al. 2011). ALKBH3 requires iron (Fe2+) for its catalytic activity (Duncan et al. 2002, Sundheim et al. 2006). ALKBH3 is ~2-fold more active on DNA containing 3-methylcytosine than 1-methyladenine (Duncan et al. 2002).
ALKBH3 (ABH3) has a preference for binding single strand DNA or RNA containing alkylation damage. ALKBH3 associates with dsDNA containing 1-methyladenine alkylation damage (1-meA-dsDNA) in the presence of ASCC3 DNA helicase. ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator complex, which unwinds dsDNA, providing an appropriate substrate for ALKBH3 (Duncan et al. 2002, Sundheim et al. 2006, Chen et al. 2010, Dango et al. 2011). ALKBH3 requires iron (Fe2+) for its catalytic activity (Duncan et al. 2002, Sundheim et al. 2006).
ALKBH2 binds alkylated DNA containing 1-methyladenine (1-meA). ALKBH2 preferentially binds double strand DNA (dsDNA) (Duncan et al. 2002, Aas et al. 2003, Chen et al. 2010). Iron (Fe2+) is needed for the catalytic activity of ALKBH2 (Duncan et al. 2002).
ALKBH3 (ABH3) has a preference for binding single strand DNA or RNA containing alkylation damage. ALKBH3 associates with dsDNA containing 1-ethyladenine alkylation damage (1-etA-dsDNA) in the presence of ASCC3 DNA helicase. ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator complex, which unwinds dsDNA, providing an appropriate subrate for ALKBH3 (Duncan et al. 2002, Sundheim et al. 2006, Chen et al. 2010, Dango et al. 2011). ALKBH3 requires iron (Fe2+) for its catalytic activity (Duncan et al. 2002, Sundheim et al. 2006).
ALKBH2 binds alkylated DNA containing 1-ethyladenine (1-etA). ALKBH2 preferentially binds double strand DNA (dsDNA) (Duncan et al. 2002, Aas et al. 2003, Chen et al. 2010). Iron (Fe2+) is needed for the catalytic activity of ALKBH2 (Duncan et al. 2002).
MGMT recognizes and binds DNA containing 6-O-methylguanine in a manner consistent with a helix-loop-wing DNA binding model, where guanine is flipped out in order to bring the methylated oxygen atom close to MGMT active site (Vora et al. 1998, Daniels et al. 2000). Weakened or distorted base-pairs formed by 6-O-methylguanine probably aid in the substrate recognition by MGMT (Duguid et al. 2005). MGMT is stabilized by Zn2+ binding (Daniels et al. 2000).
ALKBH2 binds alkylated DNA containing 3-methylcytosine (3-meC). ALKBH2 preferentially binds double strand DNA (dsDNA) (Duncan et al. 2002, Aas et al. 2003, Chen et al. 2010). Iron (Fe2+) is needed for the catalytic activity of ALKBH2 (Duncan et al. 2002).
MGMT, just like its E.coli homolog Ada, is an O-6-methylguanine transferase (Lindahl et al. 1983, Moore et al. 1994) that removes the methyl group from the guanine and transfers it to the cysteine residue at position 145 on the protein itself. MGMT thus methylated is not regenerated, as the S-methylcysteine is very stable. This is an energetically expensive approach to DNA repair as one entire protein molecule is sacrificed per lesion that is corrected in this manner (Rasimas et al. 2004, Tubbs et al. 2007, Mitra and Kaina 1993).
Fe2+- and oxoglutarate-dependent ALKB oxygenase family members are able to oxidatively demethylate alkylated DNA and RNA, thereby repairing them. The family members alpha-ketoglutarate-dependent dioxygenase FTO (FTO) and RNA demethylase ALKBH5 (ALKBH5) localise to the nucleus and can both specifically demethylate N(6)-methyladenosine (m6A) RNA, the most abundant internal modification of messenger RNA (mRNA) in higher eukaryotes (Han et al. 2010, Jia et al. 2011, Xu et al. 2014). FTO contributes to the regulation of the global metabolic rate, energy expenditure and energy homeostasis and is associated with body mass index (BMI) (Dina et al. 2007, Frayling et al. 2007, Zhang et al. 2015; reviews - Zhao et al. 2014, Merkestein & Sellayah 2015). ALKBH5 could play a role in spermatogenesis. Alkbh5-deficient male mice have increased N6-methyladenosine in mRNA and are characterised by impaired fertility (Zheng et al. 2013).
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