8k62

Structural highlights

Function

ALKB1_HUMAN Dioxygenase that acts as on nucleic acids, such as DNA and tRNA (PubMed:18603530, PubMed:27497299, PubMed:27745969). Requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:18603530, PubMed:27497299). A number of activities have been described for this dioxygenase, but recent results suggest that it mainly acts as on tRNAs and mediates their demethylation or oxidation depending on the context and subcellular compartment (PubMed:27497299, PubMed:27745969). Mainly acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs, with a preference for N(1)-methyladenine at position 58 (m1A58) present on a stem loop structure of tRNAs (PubMed:27745969). Acts as a regulator of translation initiation and elongation in response to glucose deprivation: regulates both translation initiation, by mediating demethylation of tRNA(Met), and translation elongation, N(1)-methyladenine-containing tRNAs being preferentially recruited to polysomes to promote translation elongation (PubMed:27745969). In mitochondrion, specifically interacts with mt-tRNA(Met) and mediates oxidation of mt-tRNA(Met) methylated at cytosine(34) to form 5-formylcytosine (f(5)c) at this position (PubMed:27497299). mt-tRNA(Met) containing the f(5)c modification at the wobble position enables recognition of the AUA codon in addition to the AUG codon, expanding codon recognition in mitochondrial translation (PubMed:27497299). Specifically demethylates DNA methylated on the 6th position of adenine (N(6)-methyladenosine) DNA (PubMed:30017583, PubMed:30392959). N(6)-methyladenosine (m6A) DNA is present at some L1 elements in embryonic stem cells and probably promotes their silencing (By similarity). Demethylates mRNAs containing N(3)-methylcytidine modification (PubMed:31188562). Also able to repair alkylated single-stranded DNA by oxidative demethylation, but with low activity (PubMed:18603530). Also has DNA lyase activity and introduces double-stranded breaks at abasic sites: cleaves both single-stranded DNA and double-stranded DNA at abasic sites, with the greatest activity towards double-stranded DNA with two abasic sites (PubMed:19959401). DNA lyase activity does not require alpha-ketboglutarate and iron and leads to the formation of an irreversible covalent protein-DNA adduct with the 5' DNA product (PubMed:19959401, PubMed:23577621). DNA lyase activity is not required during base excision repair and class switch recombination of the immunoglobulin heavy chain during B lymphocyte activation. May play a role in placental trophoblast lineage differentiation (By similarity).[UniProtKB:P0CB42]^{[1] [2] [3] [4] [5] [6] [7] [8]}

References

1. ↑ Westbye MP, Feyzi E, Aas PA, Vågbø CB, Talstad VA, Kavli B, Hagen L, Sundheim O, Akbari M, Liabakk NB, Slupphaug G, Otterlei M, Krokan HE. Human AlkB homolog 1 is a mitochondrial protein that demethylates 3-methylcytosine in DNA and RNA. J Biol Chem. 2008 Sep 5;283(36):25046-56. PMID:18603530 doi:10.1074/jbc.M803776200
2. ↑ Müller TA, Meek K, Hausinger RP. Human AlkB homologue 1 (ABH1) exhibits DNA lyase activity at abasic sites. DNA Repair (Amst). 2010 Jan 2;9(1):58-65. PMID:19959401 doi:10.1016/j.dnarep.2009.10.011
3. ↑ Müller TA, Andrzejak MM, Hausinger RP. A covalent protein-DNA 5'-product adduct is generated following AP lyase activity of human ALKBH1 (AlkB homologue 1). Biochem J. 2013 Jun 15;452(3):509-18. PMID:23577621 doi:10.1042/BJ20121908
4. ↑ Haag S, Sloan KE, Ranjan N, Warda AS, Kretschmer J, Blessing C, Hübner B, Seikowski J, Dennerlein S, Rehling P, Rodnina MV, Höbartner C, Bohnsack MT. NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon recognition in mitochondrial translation. EMBO J. 2016 Oct 4;35(19):2104-2119. PMID:27497299 doi:10.15252/embj.201694885
5. ↑ Liu F, Clark W, Luo G, Wang X, Fu Y, Wei J, Wang X, Hao Z, Dai Q, Zheng G, Ma H, Han D, Evans M, Klungland A, Pan T, He C. ALKBH1-Mediated tRNA Demethylation Regulates Translation. Cell. 2016 Oct 20;167(3):816-828.e16. doi: 10.1016/j.cell.2016.09.038. Epub 2016 , Oct 13. PMID:27745969 doi:http://dx.doi.org/10.1016/j.cell.2016.09.038
6. ↑ Xiao CL, Zhu S, He M, Chen, Zhang Q, Chen Y, Yu G, Liu J, Xie SQ, Luo F, Liang Z, Wang DP, Bo XC, Gu XF, Wang K, Yan GR. N(6)-Methyladenine DNA Modification in the Human Genome. Mol Cell. 2018 Jul 19;71(2):306-318.e7. doi: 10.1016/j.molcel.2018.06.015. Epub, 2018 Jul 12. PMID:30017583 doi:http://dx.doi.org/10.1016/j.molcel.2018.06.015
7. ↑ Xie Q, Wu TP, Gimple RC, Li Z, Prager BC, Wu Q, Yu Y, Wang P, Wang Y, Gorkin DU, Zhang C, Dowiak AV, Lin K, Zeng C, Sui Y, Kim LJY, Miller TE, Jiang L, Lee-Poturalski C, Huang Z, Fang X, Zhai K, Mack SC, Sander M, Bao S, Kerstetter-Fogle AE, Sloan AE, Xiao AZ, Rich JN. N(6)-methyladenine DNA Modification in Glioblastoma. Cell. 2018 Nov 15;175(5):1228-1243.e20. PMID:30392959 doi:10.1016/j.cell.2018.10.006
8. ↑ Ma CJ, Ding JH, Ye TT, Yuan BF, Feng YQ. AlkB Homologue 1 Demethylates N(3)-Methylcytidine in mRNA of Mammals. ACS Chem Biol. 2019 Jul 19;14(7):1418-1425. PMID:31188562 doi:10.1021/acschembio.8b01001