In healthy cells, huntingtin is primarily found in the cytoplasm; however, upon cellular stress, huntingtin is phosphorylated (phospho-huntingtin) at serines 13 and 16 of the amino-terminal N17 domain and shuttled into the nucleus. Such dynamism in nucleocytoplasmic translocation and post-translational modification suggests an important role for huntingtin in Huntington’s disease (HD) pathogenesis as these phenotypes propose possible mechanisms for disease progression. Huntingtin nuclear import is also facilitated by its proline-tyrosine nuclear localization signal (PY-NLS), which harbours a highly conserved intervening sequence specific to the huntingtin gene. This encouraged a proteome investigation to identify potential protein partners of the PY- NLS. Results of this study revealed that high mobility group box 1 (HMGB1), a cofactor of base excision repair, uniquely bound to the wild-type PY-NLS, but not the PY-NLS KK177/178AA mutant. Immunofluorescence microscopy in human telomerase reverse transcriptase (hTERT) immortalized fibroblast cells using HMGB1- and phospho- huntingtin-specific antibodies revealed a promising association between the two, as changes in nuclear levels of HMGB1 positively correlated with nuclear levels of phospho- huntingtin. This relationship was further confirmed by co-immunoprecipitation of HMGB1 by the PY-NLS and N17 domain. Also, when exogenous oxidative stress was introduced, increased interaction between HMGB1 and huntingtin was observed. This suggests that HMGB1 facilitates the nuclear import of huntingtin in a ROS-dependent manner, and thus, presents a novel avenue to a potential therapeutic target in HD pathogenesis. / Thesis / Master of Science (MSc)