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. Our long-term goal is to elucidate the molecular mechanisms of nucleotide excision repair (NER), to determine their role in human diseases, and to identify molecular targets for the rational design of new preventive and therapeutic strategies. Defective NER contributes to cancer, neurological disorders and aging. Additionally, NER capacity impacts tumor resistance to chemo- and radio-therapy. NER removes a wide spectrum of structurally distinct DNA lesions caused by a variety of chemical and physical agents. We and others have recently cloned a novel human gene, MMS19, which is required for NER and Pol II transcription. We have shown that the human MMS19 protein is able to complement the UV and temperature sensitivity of a yeast MMS19 deletion strain. MMS19 has no homology to other proteins and its mechanisms of function are unknown. We have also shown that MMS19 originates splice variants which can yield proteins lacking any one of three functional domains: domains A or B, within the N-terminus, or C, at the C-terminus. Moreover, our functional studies suggest that domain C is essential for MMS19 function, while domains A and B might regulate the cellular balance between NER and transcription. We hypothesize that MMS19's function is conserved from yeast to humans and that characterizing domain C protein interactions will contribute to understanding MMS19's mechanism of action. To test these hypotheses we propose: (1) to determine the function of MMS19 in mammalian cells, (2) to determine the cellular effects of newly identified MMS19 protein interactions, and (3) to examine in mammalian cells'three novel MMS19 domain-C protein-protein interactions. We will continue to explore interactions of MMS19 with candidate proteins, identified by yeast 2-hybrid screens, by determining their validity in mammalian cells and characterizing their putative functions. These studies will increase our understanding of NER and transcription, two processes known to play important roles in cancer initiation and progression.
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