DDB is a mammalian heterodimer of p127 (DDB1) and p48 (DDB2). It binds to DNA damages and interacts with a number of protein complexes, including E2F1, p300, STAGA and DNA polymerase epsilon, as well as with transactivator proteins of transforming viruses, including HB virus protein X and EB virus EBNA 2. Mutations in DDB2 give rise to xeroderma pigmentosum group E. No naturally occurring human mutations of DDB1 are known. It is likely that DDB1 and DDB2 have individual functions beyond the DDB heterodimeric DNA damage binding. The long-term goals of this project are to understand the role(s) of DDB, especially as a cancer antagonist. During the coming period it is proposed to characterize and study the DDB2 (-/-) and (-/+) mice just obtained in the laboratory and cells derived from them. Gene disruptions of DDB1 with RNAi in human cells will also be explored as will a deletion mutant of the DDB1 homologue of the fission yeast, S. pombe that was also just isolated in the laboratory. The laboratory recently showed that XP-E cells are actually abnormally resistant to UV radiation as they produce little or no p53 constitutively or in response to UV irradiation and hence do not undergo p53-mediated apoptosis. These phenomena will be further studied. Finally, a recent observation that DDB interacts with DNA polymerase epsilon will be further studied. Together these studies will help us to understand the genesis of cancers after UV irradiation, especially in xeroderma pigmentosum, as well as how viral infection can lead to cellular transformations.
