Changes in gene expression patterns are a hallmark of the aging process. Important insight into the mechanisms controlling such gene expression programs has come from the study of replicative senescence of cultured cells (eg, human diploid fibroblasts), which recapitulates many facets of cells from aging individuals. This Project has traditionally studied changes in RBP expression and function during replicative senescence. It has also examined the influence of RBPs in replicative senescence by interventions to elevate or reduce RBP levels, followed by the analysis of changes in senescence-associated mRNA expression patterns. We study if a given RBP binds a senescence-associated mRNA using a variety of in vitro binding assays (biotin pulldown, RNA EMSA, surface plasmon resonance/Biacore, etc) and assays to measure binding of endogenous molecules (ribonucleoprotein immunoprecipitation). To investigate RBP function during senescence, we employ approaches such as RBP silencing, RBP overexpression, and the identification of RBP-associated mRNAs using microarrays. We investigate whether RBPs affect the stability of target mRNAs during senescence, we measuring the steady-state levels and half-lives of the mRNAs of interest as a function of RBP abundance. We investigate whether RBPs affect the translation of target mRNAs by studying the relative assocation of the mRNA with translating polysomes and by quantifying the nascent translation rates of the encoded proteins. We also employ reporter constructs to gain additional insight into the processes modulated by RBPs and use various senescence-associated markers to examine changes in the senescence phenotype. During the past funding period, we have pursued several projects to study RBP expression in aging and age-related processes. In one of the projects, we have used tissue microarrays to study expression patterns for six key RNA-binding proteins. They showed interesting tissue and age-dependent distribution, quite distinct from the levels seen in senescent fibroblasts (Masuda et al, Aging, 2009). Further studies revealed changes in the subsets of expressed microRNAs in early-passage and senescent fibroblasts (Marasa et al., Aging, 2010). In collaborative studies, we have identified several RBPs implicated in controlling expression of the senescence-associated protein p16 (Yi et al., Nuc. Acids Res. 2010; Chang et al., Mol. Cell. Biol. 2010).
| Omer, Amr; Patel, Devang; Lian, Xian Jin et al. (2018) Stress granules counteract senescence by sequestration of PAI-1. EMBO Rep 19: |
| Kim, Kyoung Mi; Noh, Ji Heon; Bodogai, Monica et al. (2018) SCAMP4 enhances the senescent cell secretome. Genes Dev 32:909-914 |
| Tang, Hao; Wang, Hu; Cheng, Xiaolei et al. (2018) HuR regulates telomerase activity through TERC methylation. Nat Commun 9:2213 |
| Tang, Hao; Wang, Hu; Cheng, Xiaolei et al. (2018) Author Correction: HuR regulates telomerase activity through TERC methylation. Nat Commun 9:2721 |
| Noh, Ji Heon; Kim, Kyoung Mi; McClusky, Waverly G et al. (2018) Cytoplasmic functions of long noncoding RNAs. Wiley Interdiscip Rev RNA 9:e1471 |
| Basu, Sandip K; Gonit, Mesfin; Salotti, Jacqueline et al. (2018) A RAS-CaMKK?-AMPK?2 pathway promotes senescence by licensing post-translational activation of C/EBP? through a novel 3'UTR mechanism. Oncogene 37:3528-3548 |
| Lee, Hyung Chul; Jung, Seung Hee; Hwang, Hyun Jung et al. (2017) WIG1 is crucial for AGO2-mediated ACOT7 mRNA silencing via miRNA-dependent and -independent mechanisms. Nucleic Acids Res : |
| Munk, Rachel; Panda, Amaresh C; Grammatikakis, Ioannis et al. (2017) Senescence-Associated MicroRNAs. Int Rev Cell Mol Biol 334:177-205 |
| Panda, Amaresh C; Grammatikakis, Ioannis; Kim, Kyoung Mi et al. (2017) Identification of senescence-associated circular RNAs (SAC-RNAs) reveals senescence suppressor CircPVT1. Nucleic Acids Res 45:4021-4035 |
| Steri, Maristella; Orrù, Valeria; Idda, M Laura et al. (2017) Overexpression of the Cytokine BAFF and Autoimmunity Risk. N Engl J Med 376:1615-1626 |
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