Damage-specific DNA-binding protein 2 (DDB2) (DDB2)

Damage-specific DNA-binding protein 2 (DDB2) is a critical component of the UV-damaged DNA-binding (UV-DDB) complex, which plays a primary role in the initial recognition of DNA lesions caused by ultraviolet radiation (UniProt P50516). It specifically identifies cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts, initiating the global genomic nucleotide excision repair (GG-NER) pathway (PubMed: 16530710). Beyond lesion recognition, DDB2 functions as a substrate receptor for the CUL4A-RBX1 E3 ubiquitin ligase complex, facilitating the ubiquitination of histones and other repair proteins like XPC to remodel chromatin and enhance repair efficiency (PubMed: 16630892). Mutations in the DDB2 gene are the underlying cause of Xeroderma Pigmentosum complementation group E (XP-E), a condition characterized by extreme sensitivity to sunlight and a high predisposition to skin cancers (NCBI Gene: 1643). In oncology, DDB2 is often viewed as a double-edged sword; while its repair function prevents cancer initiation, its overexpression in certain tumors can lead to resistance against DNA-damaging chemotherapeutics like cisplatin (PubMed: 21737445). Consequently, the DNA-binding interface of DDB2, primarily located within its WD40 beta-propeller domain, is an area of interest for developing sensitizing agents that could inhibit DNA repair in cancer cells, thereby improving the efficacy of platinum-based treatments (PubMed: 24523406).

Other names

UV-damaged DNA-binding protein 2Xeroderma pigmentosum group E proteinXPEDDBBUV-DDB2

DDB2 recognizes and binds to UV-induced DNA lesions, such as cyclobutane pyrimidine dimers (CPDs), and recruits the CUL4A-DDB1 E3 ubiquitin ligase complex to initiate nucleotide excision repair (UniProt P50516). It facilitates the ubiquitination of XPC and histones H2A, H3, and H4, which promotes chromatin accessibility for subsequent repair factors (PubMed: 16630892).