Our long-term goal is to understand the mechanism and function of the ubiquitin- proteasome system in health and disease. This proposal focuses on the function of the XPC-Rad23 complex in DNA damage response and proteolysis. Mutations in XPC protein lead to a genetic disorder Xeroderma pigmentosum (XP) that exhibits extreme sunlight sensitivity and a strong propensity for skin cancer. XPC was known previously as a key DNA repair factor that cells employ to protect from sunlight-inflicted DNA injury.

The majority of breast cancer cases are estrogen receptor (ER?)-positive. While hormonal therapyimproves clinical outcomes for about half of patients with ER?-positive breast cancer, de novo or acquiredresistance represents a significant clinical challenge. Among several underlying mechanisms, hot-spot pointmutants of ER? are known to confer therapeutic resistance due to their estrogen-independent transcriptionalactivity. Thus, mitigating aberrant transcription activity of these ER? mutants holds promise for overcomingtherapeutic resistance in treatment of ER?-positive breast cancer.

The mTORC1 pathway regulates multiple cellular processes to promote a switch from catabolic toanabolic metabolism and is thus under tight regulatory control by growth factor signaling and nutrientsensing pathways. Dysregulation of this complex machinery is implicated in many cancers, so definingthe key mechanisms by which mTORC1 senses changes in cellular homeostasis to activate growthsignals is of great relevance. Spatial regulation of mTORC1 signaling has been recognized as a majormechanism that influences the cellular response to nutrients and the lysosome is central to thisprocess.

Uterine leiomyomas (LM; fibroids) are monoclonal neoplasms of the myometrium (MM) and represent themost frequent tumors in women worldwide. Although benign, they nonetheless account for significantgynecologic and reproductive dysfunction.