alkB homolog 1, histone H2A dioxygenase (ALKBH1)

alkB homolog 1, histone H2A dioxygenase (ALKBH1) is a 2-oxoglutarate- and Fe(II)-dependent dioxygenase found in the nucleus, cytoplasm, and mitochondria, with a primary role in the demethylation of DNA and RNA, especially at N6-methyladenine (6mA) in DNA and N1-methyladenosine (m1A) or N3-methylcytosine (m3C)/m5C/m5Cm in tRNA and RNA[1][2][3][4][5][6]. The enzyme is a member of the AlkB homolog family, originally related to bacterial DNA alkylation damage repair, but in higher eukaryotes, it carries out diverse regulatory roles in epigenetics and translation[1][2][6]. ALKBH1 is structurally unique within its family due to extended and specialized substrate recognition motifs (e.g., Flip0, Flip1, Flip2 regions and α1 helix structure), resulting in a marked preference for DNA and RNA with local unpaired regions (bulged, bubbled, or loop structures)[1][3]. Functionally, ALKBH1 regulates chromosome structure, gene expression, tRNA stability, mitochondrial translation, and cellular stress responses. It is directly implicated in cancer biology—both tumorigenesis and drug resistance—stem cell differentiation, neuroregeneration, and bone and adipose tissue development[1][3][4][6]. No approved selective inhibitors for clinical use are described as of 2024, but ALKBH1's central roles in cancer and regenerative biology make it a promising therapeutic and biomarker target. Its broad demethylation mechanisms also pose significant safety and off-target risk for drug development targeting this enzyme.

Other names

Nucleic acid dioxygenase ALKBH1ABH1alkBDNA 6mA demethylaseDNA N6-methyl adenine demethylasemRNA N(3)-methylcytidine demethylaseAlkylated DNA repair protein alkB homolog 1Alpha-ketoglutarate-dependent dioxygenase ABH1DNA lyase ABH1DNA oxidative demethylase ALKBH1tRNA N1-methyl adenine demethylasealkylation repair homolog 1other variations (see query for exhaustive list; standardize to those above for structured use)

Drugs inhibiting ALKBH1 would block demethylation of N6-mA and other adducts on nucleic acids, leading to gene silencing or altered epigenetic programming[1][3][4]. Modulation may affect translation by altering tRNA modifications[4][5][6].