DNA–protein crosslink repair enzyme

DNA–protein crosslinking enzymes are a heterogeneous group of enzymes involved in the recognition, processing, and repair of DNA–protein crosslinks—bulky, cytotoxic DNA lesions that arise when proteins become covalently bound to DNA through endogenous metabolic byproducts, environmental agents (like formaldehyde or chemotherapeutics), or failed enzymatic reactions (notably those involving DNA topoisomerases)[1][5][7]. The major mammalian DPC repair enzymes include metalloproteases such as SPRTN (also known as DVC1), which degrades the protein component of DPCs, and phosphodiesterases such as tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2, which resolve topoisomerase–DNA adducts[1][3][4][5]. Additional contributors to DPC removal include the proteasome system, nucleotide excision repair factors, and components of homologous recombination pathways[5][6]. Malfunction or inhibition of these enzymes leads to replication stress, chromosomal instability, and predisposition to cancer or progeroid syndromes[3][5][7].

Other names

DPC repair enzymesDNA–protein crosslinking proteasesDNA–protein crosslink proteases

Drugs can induce or stabilize DNA–protein crosslinks (e.g., topoisomerase poisons and formaldehyde). The enzymes in this group resolve DPCs through various mechanisms, including proteolysis of the cross-linked protein component (by SPRTN, Wss1, or proteasome), hydrolysis of covalent phosphotyrosyl bonds (by TDP1 for Topo I DPCs; TDP2 for Topo II DPCs), and polyubiquitination and SUMOylation targeting for proteasomal degradation.