The study investigates the interaction between the huntingtin (htt) protein, which is expanded in Huntington's Disease (HD), and transcription factors p53, CREB-binding protein (CBP), and mSin3a. The research reveals that the expanded htt protein (htt1p) co-aggregates with p53 in cell culture and interacts with p53 in vitro and in cell culture. Expanded htt1p represses the transcription of p53-regulated promoters, such as p21WAF1/CIP1 and MDR-1. Additionally, htt1p interacts with CBP and mSin3a, and CBP localizes to neuronal intranuclear inclusions in a transgenic mouse model of HD. These findings suggest that expanded htt may cause aberrant transcriptional regulation through its interaction with cellular transcription factors, leading to neuronal dysfunction and cell death in HD.The study investigates the interaction between the huntingtin (htt) protein, which is expanded in Huntington's Disease (HD), and transcription factors p53, CREB-binding protein (CBP), and mSin3a. The research reveals that the expanded htt protein (htt1p) co-aggregates with p53 in cell culture and interacts with p53 in vitro and in cell culture. Expanded htt1p represses the transcription of p53-regulated promoters, such as p21WAF1/CIP1 and MDR-1. Additionally, htt1p interacts with CBP and mSin3a, and CBP localizes to neuronal intranuclear inclusions in a transgenic mouse model of HD. These findings suggest that expanded htt may cause aberrant transcriptional regulation through its interaction with cellular transcription factors, leading to neuronal dysfunction and cell death in HD.