Replicative immortality is one of the hallmarks of cancer and is achieved by cancer cells through activation of telomere maintenance mechanisms. Most human cancers rely on expression of the reverse transcriptase telomerase to maintain telomere length. Cancers that do not express telomerase utilize alternative mechanisms of telomere elongation, known as ALT. Cancer cells can also trigger a telomerase-to-ALT transition to acquire resistance to telomerase-targeting therapies. One of the hallmarks of ALT is increased telomere transcription and induced expression of the telomeric noncoding RNAs TERRA which have been proposed to sustain ALT mechanisms through formation of RNA:DNA hybrids at telomeres. Furthermore, TERRA interacts with telomerase as well as ALT-relevant proteins, including ATRX, and TERRA transcripts can promote heterochromatin formation at telomeres. Thus, TERRA transcripts are critical regulators of telomere maintenance of cancer cells and represent potential therapeutic targets for cancer treatment.
We are interested in understanding the function and regulation of TERRA in human cancer cells. To this aim, we have developed a live-cell imaging assay to visualize and study endogenous TERRA transcripts expressed from a single telomere in living human cancer cells. By combining live-cell imaging with biochemical and molecular biology approaches we aim to define the dynamics of TERRA expression and localization at telomeres and characterize the role of TERRA in telomere maintenance of human cancer cells. As TERRA and telomere biology display features that are conserved throughout evolution, we are widening our studies on TERRA by working on animal models, such as D. rerio and C. elegans.
- Emilio Cusanelli, PI
- Katarina Juríková, Postdoc (H2020 MSCA IF 2020 G.A. n. 101032702 - CytoTERRA)
- Julieta Rivosecchi, Postdoc
- Nicole Bettin, PhD student
- Claudio Oss Pegorar, PhD student (in collaboration with Maria Caterina Mione)
- Alessandra Liuzzo, Master student
- Eleonora Zulian, Master student
- Luca Larini, Master student
- Marta Cantarelli Bachelor student
- Pascal Chartrand, University of Montreal, Canada
- Verena Jantsch, University of Vienna, Austria
- Maria Caterina Mione, University of Trento
- Paolo Macchi, University of Trento
- Luciano Conti, University of Trento
Savoca V, Gaiatto A, Rossi A, Mosca R, Gialdini I, Zubovic L, Macchi P, Cusanelli E. TERRA stability is regulated by RALY and polyadenylation in a telomere-specific manner. Cell Reports 2023, 42(4):112406.
Manganelli M, Grossi I, Corsi J, D’Agostino VG, Jurikova K, Cusanelli E, Molfino S, Portolani N, Salvi A, De Petro G. Expression of Cellular and extracellular TERRA, TERC and TERT in hepatocellular carcinoma. International Journal of Molecular Sciences, 2022, 23(11): 6183.
Jurikova K, De Wulf P, Cusanelli E. Nuclear periphery and telomere maintenance: TERRA joins the stage. Trends in Genetics, 2021, Mar 1.
Idilli AI, Pagani F, Kerschbamer E, Berardinelli F, Bernabé M, Cayuela ML, Piazza S, Poliani PL, Cusanelli E., Mione MC. Changes in the expression of pre-replicative complex genes in hTERT and ALT pediatric brain tumors. Cancers, 2020, 12(4).
Idilli AI, Cusanelli E., Pagani F, Berardinelli F, Bernabé M, Cayuela ML, Poliani PL, Mione MC. Expression of TERT prevents ALT in zebrafish brain tumors. Frontiers in Cell and Developmental Biology, 2020, 8(65).
Bettin N, Oss Pegorar C, Cusanelli E. The emerging roles of TERRA in telomere maintenance and genome stability. Cells, 2019, 8(3), 246.
Avogaro L, Oss Pegorar C, Bettin N, Cusanelli E. Generation of cancer cell clones to visualize telomeric repeat-containing RNA TERRA expressed from a single telomere in living cells. Journal of Visualized Experiments, 2019, (143): e58790.
Avogaro L, Querido E, Dalachi M, Jantsch M, Chartrand P, Cusanelli E. Live-cell imaging reveals the dynamics and function of single-telomere TERRA molecules in cancer cells. RNA Biology, 2018, 15(6):787-796.
Perez-Romero CA, Lalonde M, Chartrand P, Cusanelli E. Induction and relocalization of telomeric repeat-containing RNAs during diauxic shift in budding yeast. Current Genetics, 2018, 64(5):1117-1127.
Moradi-Fard S, Sarthi J, Tittel-Elmer M, Lalonde M, Cusanelli E., Chartrand P, Cobb J. Smc5/6 is a telomere-associated complex that regulates Sir4 binding and TPE. PLOS Genetics, 2016, 12(8): e1006268.
Cusanelli E.* and Chartrand P. Telomeric repeat-containing RNA TERRA: a noncoding RNA connecting telomere biology to genome integrity. Frontiers in Genetics, 2015, 6: 143. * Corresponding author.
Cusanelli E. and Chartrand P. Telomeric non-coding RNA TERRA in telomere biology. Wiley Interd. Rev. RNA, 2014, 5(3): 407-419.
Cusanelli E., Perez Romero CA, Chartrand P. Telomeric non-coding RNA TERRA is induced by telomere shortening to nucleate telomerase molecules at short telomeres. Molecular Cell, 2013, 51(6): 780-791. Highlighted by Faculty of 1000
Gallardo F*, Laterreur N*, Cusanelli E., Ouenzar F, Querido E, Wellinger RJ, Chartrand P. Live cell imaging of telomerase RNA dynamics reveals cell cycle-dependent clustering of telomerase at elongating telomeres. Molecular Cell, 2011, 44(5): 819–827
- H2020 MSCA IF 2020 - CytoTERRA -This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska- Curie grant agreement No 101032702
- 2020, My First AIRC Grant
- 2016, Rita Levi Montalcini program, (MIUR)