This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nucleotide excision repair (NER) and transcription deficiencies contribute to several human diseases and conditions, such as cancer, neurological disorders and aging. Our long-term goal is to define the NER and transcription mechanisms responsible for human disease and to identify molecular targets for the rational design of novel therapeutic agents. The proposed studies will determine the precise role of human MMS19 spliced variants in NER and transcription, identify MMS19 C-terminal interacting proteins and characterize their function. We will characterize the function of MMS19 splice variants and map the MMS19 domains required for NER and Pol II transcription. We have identified three novel proteins which, in a yeast two-hybrid system, interact specifically with MMS19 C-terminal domain. We will evaluate these protein interactions in mammalian cells and determine whether MMS19 mediates the assembly of a protein multicomplex or if these proteins bind MMS19 in a mutually exclusive manner. The MMS19 multiprotein complex will be purified from mammalian cells, MMS19 associated proteins will be identified by mass spectrometry and their role in NER and Pol II transcription will be determined. The human MMS19 gene has been recently cloned and shown to be required for effective NER and Pol II transcription. A direct link between MMS19 and human disease has not as yet been established. Nonetheless, these studies should reveal the role of various proteins in the NER and transcription processes, and they might provide important insights into the mechanisms of several human diseases and conditions.
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