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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059424-08
Application #
7230487
Study Section
Biochemistry Study Section (BIO)
Program Officer
Portnoy, Matthew
Project Start
2000-06-01
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2011-05-31
Support Year
8
Fiscal Year
2007
Total Cost
$342,575
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Itoh, Toshiki (2006) Xeroderma pigmentosum group E and DDB2, a smaller subunit of damage-specific DNA binding protein: proposed classification of xeroderma pigmentosum, Cockayne syndrome, and ultraviolet-sensitive syndrome. J Dermatol Sci 41:87-96
Itoh, Toshiki; Linn, Stuart (2005) The fate of p21CDKN1A in cells surviving UV-irradiation. DNA Repair (Amst) 4:1457-62
Itoh, Toshiki; Cado, Dragana; Kamide, Ryoichi et al. (2004) DDB2 gene disruption leads to skin tumors and resistance to apoptosis after exposure to ultraviolet light but not a chemical carcinogen. Proc Natl Acad Sci U S A 101:2052-7
Sancar, Aziz; Lindsey-Boltz, Laura A; Unsal-Kacmaz, Keziban et al. (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73:39-85
Nichols, Anne F; Itoh, Toshiki; Zolezzi, Francesca et al. (2003) Basal transcriptional regulation of human damage-specific DNA-binding protein genes DDB1 and DDB2 by Sp1, E2F, N-myc and NF1 elements. Nucleic Acids Res 31:562-9
Itoh, Toshiki; O'Shea, Cristin; Linn, Stuart (2003) Impaired regulation of tumor suppressor p53 caused by mutations in the xeroderma pigmentosum DDB2 gene: mutual regulatory interactions between p48(DDB2) and p53. Mol Cell Biol 23:7540-53
Asahara, Hitomi; Li, Ying; Fuss, Jill et al. (2003) Stimulation of human DNA polymerase epsilon by MDM2. Nucleic Acids Res 31:2451-9
Zolezzi, Francesca; Fuss, Jill; Uzawa, Satoru et al. (2002) Characterization of a Schizosaccharomyces pombe strain deleted for a sequence homologue of the human damaged DNA binding 1 (DDB1) gene. J Biol Chem 277:41183-91
Itoh, T; Nichols, A; Linn, S (2001) Abnormal regulation of DDB2 gene expression in xeroderma pigmentosum group E strains. Oncogene 20:7041-50
Itoh, T; Linn, S (2001) XP43TO, previously classified as xeroderma pigmentosum Group E, should be reclassified as xeroderma pigmentosum variant. J Invest Dermatol 117:1672-4