DNA oxidative demethylase ALKBH2

Definition:

Dioxygenase that repairs alkylated nucleic acid bases by direct reversal oxidative dealkylation. Can process both double-stranded (ds) and single-stranded (ss) DNA substrates, with a strong preference for dsDNA. Uses molecular oxygen, 2-oxoglutarate and iron as cofactors to oxidize the alkyl groups that are subsequently released as aldehydes, regenerating the undamaged bases. Probes the base pair stability, locates a weakened base pair and flips the damaged base to accommodate the lesion in its active site for efficient catalysis. Repairs monoalkylated bases, specifically N1-methyladenine and N3-methylcytosine, as well as higher order alkyl adducts such as bases modified with exocyclic bridged adducts known as etheno adducts including 1,N6-ethenoadenine, 3,N4-ethenocytosine and 1,N2-ethenoguanine. Acts as a gatekeeper of genomic integrity under alkylation stress. Efficiently repairs alkylated lesions in ribosomal DNA (rDNA). These lesions can cause ss- and dsDNA strand breaks that severely impair rDNA transcription. In a response mechanism to DNA damage, associates with PCNA at replication forks to repair alkylated adducts prior to replication.

References:

[1]. Tod Duncan, et al. Reversal of DNA alkylation damage by two human dioxygenases. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16660-5. [Content Brief]

[2]. Cai-Guang Yang, et al. Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA. Nature. 2008 Apr 24;452(7190):961-5. [Content Brief]

[3]. Pishun Li, et al. ABH2 couples regulation of ribosomal DNA transcription with DNA alkylation repair. Cell Rep. 2013 Aug 29;4(4):817-29. [Content Brief]

[4]. Dong-Hyun Lee, et al. Repair of methylation damage in DNA and RNA by mammalian AlkB homologues. J Biol Chem. 2005 Nov 25;280(47):39448-59. [Content Brief]

[5]. Daria Zdżalik, et al. Differential repair of etheno-DNA adducts by bacterial and human AlkB proteins. DNA Repair (Amst). 2015 Jun;30:1-10. [Content Brief]

[6]. Chengqi Yi, et al. Duplex interrogation by a direct DNA repair protein in search of base damage. Nat Struct Mol Biol. 2012 Jun 3;19(7):671-6. [Content Brief]

[7]. Per Arne Aas, et al. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature. 2003 Feb 20;421(6925):859-63. [Content Brief]

[8]. Karin M Gilljam, et al. Identification of a novel, widespread, and functionally important PCNA-binding motif. J Cell Biol. 2009 Sep 7;186(5):645-54. [Content Brief]

[9]. Baoen Chen, et al. Mechanistic insight into the recognition of single-stranded and double-stranded DNA substrates by ABH2 and ABH3. Mol Biosyst. 2010 Nov;6(11):2143-9. [Content Brief]

[10]. Dragony Fu, et al. The interaction between ALKBH2 DNA repair enzyme and PCNA is direct, mediated by the hydrophobic pocket of PCNA and perturbed in naturally-occurring ALKBH2 variants. DNA Repair (Amst). 2015 Nov;35:13-8. [Content Brief]

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