Damage-specific DNA binding protein 2 (DDB2)

Damage-specific DNA binding protein 2 (DDB2) is a critical component of the UV-DDB complex, serving as a primary sensor for UV-induced DNA damage, including cyclobutane pyrimidine dimers and 6-4 photoproducts [UniProt, 2024]. It initiates the Global Genome Nucleotide Excision Repair (GG-NER) pathway by recognizing lesions and recruiting downstream repair factors like XPC, while also acting as a substrate receptor for the CUL4-DDB1 E3 ubiquitin ligase complex to facilitate chromatin remodeling through histone ubiquitination [NIH, 2022]. Mutations in the DDB2 gene are the underlying cause of Xeroderma Pigmentosum complementation group E (XP-E), a condition characterized by extreme UV sensitivity and a high risk of skin cancer [NIH, 2006]. In oncology, DDB2 is often overexpressed and contributes to chemoresistance by enhancing the repair of therapy-induced DNA damage and suppressing apoptosis in cancers such as breast, lung, and liver [NIH, 2025]. The DDB2–DNA interface has emerged as a specific therapeutic target; for example, the drug lapatinib has been shown to bind this region, disrupting DDB2's association with DNA and promoting its degradation [NIH, 2025]. This disruption inhibits the initiation of DNA repair and sensitizes cancer cells to DNA-damaging chemotherapeutics like doxorubicin, highlighting the potential of targeting the DDB2–DNA interface for chemosensitization in various malignancies [NIH, 2025].

Other names

DDBBUV-DDB2p48XPEDamage-specific DNA-binding protein 2DDB2–DNA interface

Lapatinib acts as a noncanonical inhibitor by binding directly to the DNA-binding region of DDB2, thereby disrupting the DDB2–DNA interface. This interaction prevents DDB2 from associating with chromatin and promotes its proteasomal degradation, which inhibits the initiation of nucleotide excision repair (NER) and sensitizes cancer cells to DNA-damaging chemotherapeutic agents.