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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG032134-05
Application #
8116000
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (O6))
Program Officer
Guo, Max
Project Start
2007-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$279,114
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Peña, AndreAna N; Tominaga, Kaoru; Pereira-Smith, Olivia M (2011) MRG15 activates the cdc2 promoter via histone acetylation in human cells. Exp Cell Res 317:1534-40
Martrat, Griselda; Maxwell, Christopher M; Tominaga, Emiko et al. (2011) Exploring the link between MORF4L1 and risk of breast cancer. Breast Cancer Res 13:R40
Chen, Meizhen; Pereira-Smith, Olivia M; Tominaga, Kaoru (2011) Loss of the chromatin regulator MRG15 limits neural stem/progenitor cell proliferation via increased expression of the p21 Cdk inhibitor. Stem Cell Res 7:75-88
Luco, Reini F; Pan, Qun; Tominaga, Kaoru et al. (2010) Regulation of alternative splicing by histone modifications. Science 327:996-1000
Tominaga, Kaoru; Tominaga, Emiko; Ausserlechner, Michael J et al. (2010) The cell senescence inducing gene product MORF4 is regulated by degradation via the ubiquitin/proteasome pathway. Exp Cell Res 316:92-102
Huichalaf, Claudia; Sakai, Keiko; Jin, Bingwen et al. (2010) Expansion of CUG RNA repeats causes stress and inhibition of translation in myotonic dystrophy 1 (DM1) cells. FASEB J 24:3706-19
Chen, Meizhen; Tominaga, Kaoru; Pereira-Smith, Olivia M (2010) Emerging role of the MORF/MRG gene family in various biological processes, including aging. Ann N Y Acad Sci 1197:134-41
Zhang, Hongjun; Li, Yishi; Yang, Junsheng et al. (2010) Conditional inactivation of MRG15 gene function limits survival during larval and adult stages of Drosophila melanogaster. Exp Gerontol 45:825-33
Chen, Meizhen; Takano-Maruyama, Masumi; Pereira-Smith, Olivia M et al. (2009) MRG15, a component of HAT and HDAC complexes, is essential for proliferation and differentiation of neural precursor cells. J Neurosci Res 87:1522-31
Garcia, Sandra N; Pereira-Smith, Olivia (2008) MRGing chromatin dynamics and cellular senescence. Cell Biochem Biophys 50:133-41