Date of Award


Degree Type


Degree Name

Master of Science


Pharmacology and Toxicology


Dr. Marc Tini

Second Advisor

Dr. Lina Dagnino

Third Advisor

Dr. Joe Torchia


Thymine DNA glycosylase is an essential component of base excision repair that excises mispaired thymine and uracil in the CpG context. This activity makes TDG an important factor in CpG dinucleotide maintenance. Through its association with the transcriptional coactivator proteins CBP∕p300 and other transcription factors, TDG has also been implicated in the regulation of gene expression. Here we delineate two distinct Small Ubiquitin-like Modifier protein (SUMO) binding domains in mouse TDG and demonstrate that this activity is inhibited by the hydrophilic amino-terminal region of TDG via DNA binding. The SUMO-binding activity of TDG, rather than binding to unmodified PML, was found to be essential for its localization to PML oncogenic domains (PODs). CBP∕p300 have been identified as POD-associated proteins, and have also been implicated in cell cycle regulation. Given its association with CBP∕p300, we postulated that TDG may be regulated in a cell cycle dependent manner. In this study, we demonstrated that cellular TDG levels diminish in S phase of the cell cycle, and this depletion may occur as a result of proteasome-mediated degradation. During mitosis cellular TDG levels were found to increase from those found in S phase, and in an interesting observation, TDG was excluded from condensed chromatin during all phases of mitosis. We also investigated whether TDG may be involved in regulating cell cycle progression by measuring cellular proliferation in stable cell lines expressing decreased levels of TDG. These studies revealed that TDG downregulation causes an increase in cellular proliferation consistent with a plausible role of TDG in regulating the cell cycle. Collectively, these findings have elucidated the SUMO-mediated mechanisms of TDG subnuclear localization, and have implicated TDG in cell cycle regulation in addition to its well established role in DNA repair.



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