Role of MRG15 in Chromatin Changes During Cell Senescence and In Vivo Aging

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The overall goal of this project is to elucidate the role of chromatin remodeling during in vitro and in vivo aging. It is becoming increasingly clear that chromatin remodeling is essential for gene expression regulation and organization of DMA structure to allow for repair of DNA damage. MRG15, which is clearly involved in various aspects of chromatin remodeling, therefore serves as an excellent model gene for the study of the importance of changes in chromatin structure on gene expression and DNA repair during the aging process. MRG15 was cloned in our laboratory in the course of our studies of cellular aging, as one of three members of the MORF/MRG family of genes that is expressed. It shares common motifs with MORF4 and MRGX that include a leucine zipper, HLH region and nuclear localization signal sequences, which uggest these proteins will be involved in transcriptional regulation via protein-protein interactions. However, n the N-terminal domain of only MRG15 is a chromodomain motif, which is highly similar to that in the ms!3 (male specific lethal) gene of Drosophila, which is required for activation of transcription of the entire X chromosome in male flies, the dosage compensation mechanism. This chromodomain has now been mplicated as essential for recruitment of MRG15 as a component of the Tip60 histone acetyltranserase complex to sites where chromatin remodeling must occur. This includes regions where transcription activation is to occur and also sites of damaged DNA. Chromatin remodeling precedes the recruitment of nuclear protein complexes involved in transcription or DNA repair. MRG15 is a highly conserved protein and s present in yeast to human. The protein components of the complexes it associates with are also highly conserved. It is therefore not surprising that deletion of this gene in mice or Drosophila results in embryonic ethality. In this proposal we plan to determine the role of MRG15 in cell proliferation control and DNA damage repair using both cell culture systems, young and old C57BI6 mice and the MRG15 heterozygous mouse model. We will characterize the various protein complexes involved, their changes during in vitro and n vivo aging and the impact of these changes on function of cells and tissues. The results will not only tie ogether in vitro and in vivo information, but also increase our knowledge of how and when nuclear protein omplexes act and better define the role of chromatin remodeling during aging.