DDB2 Inhibitors

DNA damage-binding protein 2 (DDB2) plays a pivotal role in the cellular response to ultraviolet (UV) radiation-induced DNA lesions and other forms of DNA damage. As a critical component of the damaged DNA recognition machinery, DDB2 is primarily responsible for initiating nucleotide excision repair (NER) by facilitating the recognition and recruitment of other key repair factors to the lesion sites. DDB2 is a versatile protein that operates in concert with the DDB1-CUL4A-RBX1 ubiquitin ligase complex, where it acts as a substrate receptor, mediating the ubiquitination and subsequent degradation of target proteins involved in cell cycle regulation and DNA repair pathways. This multifaceted functionality underscores its significance in maintaining genomic integrity and disrupting the accumulation of DNA mutations that can lead to cancer and other genetic diseases. Inhibition of DDB2 represents a pivotal research avenue with implications for understanding the intricate network of DNA damage response and repair mechanisms. Strategies to impede DDB2 function predominantly focus on disrupting its interaction with damaged DNA or the formation of the DDB1-CUL4A-RBX1 complex. Targeted inhibition could involve the design of small molecules or peptides that competitively bind to DDB2's DNA-binding domain, blocking its association with DNA lesions and thereby impairing the initiation of NER. Additionally, efforts could be directed toward disrupting the interaction between DDB2 and the DDB1-CUL4A-RBX1 complex, through the development of chemical compounds that interfere with the binding interfaces between these proteins. By dissecting the intricate mechanisms underlying DDB2 inhibition, researchers aim to gain insights into the broader field of DNA damage response, offering prospects for innovative strategies to combat genomic instability and its associated pathologies.