Telomerase is composed of a catalytic protein subunit TERT and an RNA subunit TERC that together produce a specialized reverse transcriptase that performs telomere elongation during the S phase of the cell cycle. TERT expression is down regulated in most human somatic cells, leading to progressive telomere shortening and eventual cell cycle arrest. In vitro experiments have shown that the TERT-TERC complex is sufficient to reconstitute the enzymatic telomerase activity. However, recent reports have demonstrated that telomerase interacts with other proteins that regulate its telomere elongating activity. Moreover, emerging evidence suggests that TERT has functions unrelated to its telomere elongation activity that affect cell life span, stem cell differentiation and the response to DNA damage. The Hahn laboratory has recently identified a second RNA that binds to hTERT, RNA component of mitochondrial RNA processing endoribonuclease (RMRP), which when bound to TERT forms a distinct enzymatic complex that exhibits RNA dependent RNA polymerase (RdRP) activity. Interestingly, the RMRP RNA has been shown to be mutated in the pleiotropic syndrome Cartilage-Hair Hypoplasia (CHH). Using molecular, cell biological and biochemical approaches, I propose to analyze the effect of manipulating RMRP expression on the telomeric and non-telomeric functions of hTERT. These studies will permit me to identify the role of the TERT-RMRP complex in both telomere and extra-telomere biology.
The majority of human cancer cells overexpress the catalytic unit of telomerase, TERT, and thus, small molecules targeting telomerase are a promising strategy for treating cancer. Indeed, modified oligonucleotides targeting telomerase have entered clinical trials. TERT contributes to cell transformation, at least in part, through its role in telomere elongation. However, accumulating evidence suggests that TERT may have functions that are not related to maintaining telomere structure. My mentor's laboratory has recently identified a second non-coding RNA molecule, RMRP that binds to hTERT and has a different enzymatic activity. RMRP RNA is mutated in the pleiotropic syndrome Cartilage-Hair Hypoplasia (CHH), a syndrome characterized by short stature, fine sparse blond hair, and hypoplastic anemia. CHH is also associated with defective cellular immunity, gastrointestinal dysfunction, and a predisposition to cancer. Understanding the role of this distinct TERT complex on the telomeric and non- telomeric functions of TERT will provide important insights to the biology of TERT in both aging and cancer.
|Lovejoy, Courtney A; Li, Wendi; Reisenweber, Steven et al. (2012) Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet 8:e1002772|
|Rosenbluh, Joseph; Nijhawan, Deepak; Cox, Andrew G et al. (2012) Î²-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 151:1457-73|
|Rosenbluh, Joseph; Nijhawan, Deepak; Chen, Zhao et al. (2011) RMRP is a non-coding RNA essential for early murine development. PLoS One 6:e26270|
|Stenglein, Mark D; Burns, Michael B; Li, Ming et al. (2010) APOBEC3 proteins mediate the clearance of foreign DNA from human cells. Nat Struct Mol Biol 17:222-9|
|Demorest, Zachary L; MacDuff, Donna A; Brown, William L et al. (2010) The interaction between AID and CIB1 is nonessential for antibody gene diversification by gene conversion or class switch recombination. PLoS One 5:e11660|
|Refsland, Eric W; Stenglein, Mark D; Shindo, Keisuke et al. (2010) Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction. Nucleic Acids Res 38:4274-84|