ALKBH2

ALKBH2 Full Name

alkB, alkylation repair homolog 2 (E. coli)

ALKBH2 Introduction

AlkB homolog 2 (ALKBH2) is a fundamental DNA repair enzyme belonging to the mammalian AlkB family of non-heme Fe(II)- and 2-oxoglutarate-dependent dioxygenases. Functioning as a direct reversal repair protein, ALKBH2 is primarily localized in the cell nucleus where it acts as a critical gatekeeper of genomic integrity. While its closely related family members (such as ALKBH3 or ALKBH1) often target single-stranded DNA or RNA, ALKBH2 is structurally distinct in its strict preference for repairing lesions within double-stranded DNA (dsDNA). It contains specific DNA-binding motifs, including a crucial hydrophobic hairpin loop, that allow it to grasp the complementary DNA strand and firmly anchor itself to the double helix.

Figure 1. Average structure of AlkBH2−dsDNA (A) and the view of the active site (B). (Source: Waheed SO, et al. 2020)

Mechanistically, ALKBH2 continuously interrogates the DNA duplex by sliding along the minor groove to detect structurally unstable base pairs caused by alkylation damage. Its primary physiological substrates are cytotoxic and mutagenic methylation lesions, most notably 1-methyladenine (1meA) and 3-methylcytosine (3meC). Upon locating a damaged base, ALKBH2 employs a sophisticated "base-flipping" mechanism. It forcefully extrudes the aberrantly methylated base out of the DNA helix and into its active site, while simultaneously inserting an aromatic amino acid "finger" (Phe102) into the DNA stack to prevent the double helix from collapsing. Using molecular oxygen and 2-oxoglutarate, ALKBH2 then catalyzes the oxidative dealkylation of the lesion, releasing the methyl group as formaldehyde and perfectly restoring the undamaged DNA base without breaking the DNA backbone.

Clinically, the profound DNA-protecting capabilities of ALKBH2 intimately link it to cancer pathogenesis and therapeutic resistance. Because tumor cells are frequently subjected to high levels of endogenous oxidative and alkylation stress, they often hijack ALKBH2 to ensure their own survival. ALKBH2 is significantly upregulated in various aggressive malignancies, including glioblastoma multiforme, bladder cancer, and urothelial carcinomas. More importantly, overexpression of ALKBH2 serves as a major driver of clinical chemoresistance. By rapidly repairing the severe DNA damage inflicted by clinical alkylating agents—such as temozolomide (TMZ) used in brain tumors—ALKBH2 heavily prevents chemotherapy-induced tumor cell apoptosis. Consequently, the selective inhibition of ALKBH2 is currently being explored as a highly promising strategy to re-sensitize resistant tumors to standard DNA-damaging therapies.

Alternate Names for ALKBH2

ALKBH2; alkB, alkylation repair homolog 2 (E. coli); alpha-ketoglutarate-dependent dioxygenase alkB homolog 2; ABH2; MGC90512; oxy DC1; 2OG-Fe(II) oxy DC1; alkylated DNA repair protein alkB homolog 2; FLJ99103;

• 1. Waheed SO, et al. Role of Structural Dynamics in Selectivity and Mechanism of Non-heme Fe(II) and 2-Oxoglutarate-Dependent Oxygenases Involved in DNA Repair. ACS Cent Sci. 2020 May 27;6(5):795-814.
  2. Johannessen TC, et al. The DNA repair protein ALKBH2 mediates temozolomide resistance in human glioblastoma cells. Neuro Oncol. 2013 Mar;15(3):269-78.