DDB2

DNA damage-binding protein 2 (DDB2), also known as UV-DDB2 or p48, is a eukaryotic protein encoded by the DDB2 gene in humans. It forms a heterodimer with DDB1 to create the ultraviolet-damage DNA-binding (UV-DDB) complex, which rapidly recognizes ultraviolet-induced DNA lesions and initiates global genomic nucleotide excision repair.

DDB2 plays a primary role in recognizing lesions generated by UV irradiation, with a higher affinity for 6-4 photoproducts and a capacity to assist in recognizing cyclobutane pyrimidine dimers. By binding damaged DNA, the UV-DDB complex helps recruit downstream repair factors, including the XPC-HR23B complex, and can aid in chromatin remodeling to facilitate repair.

Mechanistically, DDB2 is involved in the CRL4DDB2 E3 ubiquitin ligase pathway, in which the complex ubiquitylates substrates such as XPC and DDB2 itself in response to DNA damage. This ubiquitination regulates repair factor turnover and the progression of nucleotide excision repair.

Clinical significance of DDB2 is highlighted by xeroderma pigmentosum group E (XP-E), a disorder characterized by extreme sensitivity to UV light and a markedly increased risk of skin cancers due to impaired GG-NER. DDB2 is widely expressed and localized to the nucleus, reflecting its central role in maintaining genomic integrity.

In addition to its repair functions, DDB2 is involved in DNA damage signaling and chromatin context of repair. Its activity is conserved across vertebrates and, in various organisms, contributes to the cellular response to genotoxic stress.