TDP2 Human

TDP2 is the only known enzyme that can hydrolyze 5’-tyrosyl-DNA adducts, which are formed when topoisomerase II creates a covalent bond between its active site tyrosine and the DNA backbone. The enzyme’s catalytic site is similar to that of APE1 endonuclease and consists of at least four essential residues: Asparagine-120, Glutamic acid-152, Aspartic acid-262, and Histidine-351 . These residues, along with two divalent metal ions (typically magnesium or manganese), are crucial for the enzyme’s activity.

Recombinant human TDP2 preferentially processes single-stranded DNA ends or duplex DNA with a four-base pair overhang . The enzyme requires a phosphotyrosyl linkage for its activity and can tolerate an extended group attached to the tyrosine. TDP2’s activity is significantly reduced or abolished when any of the four essential residues are mutated to alanine .

TDP2 is critical for the repair of trapped topoisomerase complexes. It removes a variety of covalent adducts from DNA through the hydrolysis of a 5’-phosphodiester bond, resulting in DNA with a free 5’ phosphate . This activity allows for the repair of topoisomerase II-induced DNA double-strand breaks without the need for nuclease activity, creating a “clean” double-strand break with 5’-phosphate termini that are ready for ligation .

Beyond its role in DNA repair, TDP2 is involved in several other cellular processes. It associates with CD40, tumor necrosis factor receptor-75, and tumor necrosis factor receptor-associated factors (TRAFs), and inhibits nuclear factor-kappa-B activation . TDP2 also plays roles in HIV viral genome integration, cell proliferation, ribosome biogenesis, and the RNA-DNA damage response .