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Tumor-prone phenotype of the DDB2-deficient mice
Taewon Yoon1, Amit Chakrabortty, Roberta Franks
1Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois at Chicago, 900 S. Ashland Ave., Chicago, IL-60607, USA.
Abstract:
DDB2 is an essential subunit of the damaged-DNA recognition factor DDB, which is involved in global genomic repair in human cells. Moreover, DDB2 is mutated in the repair-deficiency disease xeroderma pigmentosum (Group E). Expression of DDB2 in human cells is induced by P53, BRCA1 and by ionizing radiation. The DDB2 protein associates with transcriptional activator and coactivator proteins. In addition, DDB2 in conjunction with DDB1 associates with cullin 4A and the Cop9/signalosome. We generated a mouse strain deficient for DDB2 (DDB2-/-). Consistent with the human disease (XP-E), the DDB2-/- mice were susceptible to UV-induced skin carcinogenesis. We observed a significant difference in the initial rate of cyclobutane pyrimidine dimer (CPD)-removal from the skin following UV irradiation. Also, the DDB2-deficient mice exhibited a significantly reduced life span compared to their wild-type littermates. Moreover, unlike other XP-deficient mice, the DDB2-deficient mice developed spontaneous malignant tumors at a high rate between the ages of 20 and 25 months. The observations suggest that, in addition to DNA repair, the other interactions of DDB2 are significant in its tumor suppression function.
Insights
Damaged-DNA binding protein 2 (DDB2) is crucial for DNA repair and preventing UV-induced skin cancer. Mice lacking DDB2 showed increased cancer susceptibility, shorter lifespans, and spontaneous tumor development, highlighting its broader tumor suppression role.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- DDB2 is a key component of the DNA damage recognition factor DDB, essential for global genomic repair.
- Mutations in DDB2 cause xeroderma pigmentosum (XP-E), a DNA repair deficiency disease.
- DDB2 expression is induced by p53, BRCA1, and ionizing radiation, and it interacts with transcriptional regulators and the cullin 4A/Cop9/signalosome complex.
Purpose of the Study:
- To investigate the in vivo function of DDB2 in DNA repair and tumor suppression using a DDB2-deficient mouse model.
- To compare the UV response and tumor development in DDB2-/- mice with human XP-E patients and other XP mouse models.
Main Methods:
- Generation of a DDB2-deficient (DDB2-/-) mouse strain.
- Assessment of UV-induced skin carcinogenesis susceptibility.
- Measurement of cyclobutane pyrimidine dimer (CPD) removal rates in the skin post-UV irradiation.
- Evaluation of lifespan and spontaneous tumor development in DDB2-/- mice.
Main Results:
- DDB2-/- mice exhibited increased susceptibility to UV-induced skin carcinogenesis, mirroring human XP-E.
- A significant delay in initial CPD removal from the skin was observed in DDB2-/- mice after UV exposure.
- DDB2-/- mice had a significantly reduced lifespan and developed spontaneous malignant tumors at a high rate (20-25 months).
Conclusions:
- DDB2 plays a critical role in DNA repair, specifically in removing UV-induced DNA damage.
- DDB2 functions as a tumor suppressor, independent of its DNA repair role, as evidenced by spontaneous tumor formation.
- The findings suggest that DDB2's interactions beyond DNA repair are vital for its tumor suppression capabilities.
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