DNA damage-binding protein 2 (DDB2) (DDB2)

DNA damage-binding protein 2 (DDB2), also known as the p48 subunit, is a critical component of the UV-damaged DNA-binding (UV-DDB) complex, which initiates the global genome nucleotide excision repair (GG-NER) pathway [1, 8]. It primarily functions as a damage sensor that recognizes ultraviolet-induced DNA lesions, such as cyclobutane pyrimidine dimers and 6-4 photoproducts, and recruits the CUL4A-DDB1 E3 ubiquitin ligase complex to the site of damage [3, 7]. Within this complex, DDB2 acts as a substrate receptor, mediating the ubiquitination of histones and repair factors like XPC to facilitate chromatin remodeling and efficient DNA repair [7, 11]. Beyond its role in NER, DDB2 is involved in regulating the cell cycle, apoptosis, and premature senescence through interactions with p53, p21, and E2F1 [1, 10, 14]. In human health, mutations in the DDB2 gene cause Xeroderma pigmentosum group E (XPE), a condition characterized by extreme sensitivity to sunlight and a high risk of skin cancer [2, 8]. In oncology, DDB2 exhibits a context-dependent role, acting as a tumor suppressor in normal tissues but often contributing to chemoresistance and poor prognosis in established malignancies by enhancing DNA repair capacity [6, 9, 14]. Consequently, DDB2 is an emerging therapeutic target, with strategies such as using lapatinib to disrupt its DNA-binding activity being explored to sensitize tumors to chemotherapy and PARP inhibitors [4, 9].

Other names

Damage-specific DNA-binding protein 2p48 subunit of UV-DDBXeroderma pigmentosum group E proteinDDBBUV-XPE

Disruption of DDB2-DNA interaction, Inhibition of nucleotide excision repair, Chemosensitization, Radiosensitization, Regulation of p53-mediated apoptosis