Investigation of the function of UV damaged DNA binding protein 1 (DDB1) in mammalian systems.
Published: 2005
Language: eng
Number of pages: 258
Description: UV-damaged DNA binding protein 1 (DDB1) is a highly conserved protein found in many plants and animals. DDB1 interacts with UV-damaged DNA binding protein 2 (DDB2) or Cockayne syndrome protein A (CSA) both of which participate in DNA nucleotide excision repair. DDB1 has been implicated in transcription, and functions in ubiquitin ligase complexes for stimulus response. Plant forms of DDB1 ubiquitinate c-Jun proteins during photomorphogenesis. Yeast DDB1 regulates S-phase through dNTP synthesis, a function retained in human DDB1 regulation of DNA replication by CDT1 ubiquitination. This study investigates DDB1 functions by gene-deletion and gene-depletion in mouse and human cells. DDB1 is expressed in most cells/organs and is located in meiotic and mitotic spindles. Complete absence of the mouse Ddb1 gene is peri-implantation embryonic lethal (E5), and ddb1 (-/-) cell lines fail to grow. Heterozygous  ddb1 (+/-) mice show haploinsufficiency and premature aging symptoms (alopecia, kyphosis, tumours) concurrent with diminished DDB1 protein levels. siRNA-mediated depletion of gDDB1 causes decreased proliferation, inhibition of DNA repair, and increased cell death in cultured cells. Biochemical studies show novel DDB1 interactions with replication and transcription factors, and a transcription elongation complex. Investigation of DDB1 loss of function suggests that DDB1 is involved in many processes including replication and transcription-coupled repair. Overall, these results suggest that DDB1 maintains cellular homeostasis by its roles in cell proliferation, cell cycle control, transcription, and inhibition of apoptosis, as well as DNA repair.
Notes: Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5246.

Thesis (Ph.D.)--University of Toronto, 2005.

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