Telomere Length Regulation
We focus on understanding the molecular mechanisms underlying telomere length regulation and how telomere length can be manipulated to control cell division.
Research Overview
Telomeres are repetitive sequences of DNA bound to a complex of telomere-specific proteins that function to cap the ends of linear chromosomes, thus maintaining chromosome stability. Telomeric DNA is gradually eroded with each round of cell division, limiting the number of times a normal cell can divide. Telomere maintenance is vital for the continued growth of tumour cells and occurs either by activation of the enzyme telomerase, or by recombination-mediated telomere replication referred to as alternative lengthening of telomeres (ALT).
Lab Head
Hilda Pickett
Head, Telomere Length Regulation Unit.
Available for Student
Supervision
Email
[email protected]
Professor Hilda Pickett is Head of the Telomere Length Regulation Unit at CMRI. Potential PhD applicants should contact Prof Pickett for specific project details.
Team Members
Alexander Sobinoff
Senior Research Officer
BBiotech (Hons), PhD , Postdoctoral Fellow
Vivian SIlva Kahl
Research Officer
BSc, MSc, PhD, Postdoctoral Fellow
Christopher Nelson
Research Officer
BS, PhD, Postdoctoral Fellow
Research Projects
Telomeres
Telomeres are nucleoprotein structures at the ends of linear chromosomes that contribute to the maintenance of chromosome integrity. Telomere length regulation involves an intricate balance between lengthening and shortening processes, which ultimately determines the proliferative capacity of a cell. Telomere length dysregulation can result in cancer, or in an emerging spectrum of premature ageing disorders. The Pickett lab is investigating the mechanism of telomere rapid deletion by telomere trimming, how telomere length contributes to cell proliferation and human health, and how telomere maintenance mechanisms become activated in cancer cells. The Pickett lab is also using next generation sequencing technologies to study telomere length and telomere sequence content. This research will underpin further clinical studies, and will impact upon cancer control and the treatment of short telomere syndromes.
Telomere Trimming
Telomere rapid deletion by telomere trimming involves homologous recombination-mediated resolution of the terminal t-loop, and functions to prevent the persistence of over-lengthened telomeres. Telomere trimming does not elicit a DNA damage response, indicating that the mechanism is a normal well-regulated cellular process. We have identified telomere trimming in normal human cells of germline and somatic origin and in mouse somatic tissues, and are currently investigating telomere trimming in other proliferating cells. In addition, we are characterising the functional proteins and cell signalling responses that regulate telomere trimming.
Telomere Maintenance Mechanisms
Short telomeres are associated with adverse health outcomes, including increased risk of multiple diseases such as cardiovascular disease and cancer. Telomeres can be extended by two known mechanisms: the enzyme telomerase, which uses an intrinsic RNA template sequence to reverse transcribe telomeric repeats onto the chromosome end, and the Alternative Lengthening of Telomeres (ALT) pathway, a recombination-dependent replication mechanism that utilises a variety of DNA repair pathways to extend chromosome ends. Telomerase is active in the human germline, early in embryogenesis and in some stem and progenitor cell populations to enable increased proliferative capacity. Cancer cells activate either telomerase or ALT to repair eroded or dysfunctional telomeres to ensure proliferative immortality. The Pickett lab is investigating telomerase activation, as well as the processes that regulate telomerase biogenesis and recruitment. The Pickett lab also works extensively on characterising the mechanism of ALT-mediated telomere lengthening in cancer cells.
Telomere Sequence Content
Telomeres are thought to comprise almost exclusively hexameric TTAGGG repeats. The Pickett lab have been using whole genome sequencing to demonstrate that telomeres also contain abundant variant telomeric repeats, which contribute to telomere biology. We are currently employing next generation sequencing techniques to accurately measure telomere sequence content, and using this information to characterise telomere length and telomere maintenance mechanisms in large-scale whole genome sequencing datasets.
Past lab members
Fiona Yang (PhD Student) 2015-2020
Joshua Allen (Research Assistant) 2012-2020
Michael Lee (Research Assistant and PhD Student) 2013-2019
Advaitha Jagadeesan (Honours Student) 2019
Christopher Tomlinson (Posdoctoral Fellow) 2015-2017
Monica Brygula (PhD Student) 2012-2016
Anagha Killedar (Research Assistant) 2013-2015
Nunki Hassan (Honours Student) 2014
Dimitri Conomos (PhD Student) 2010-2014
Michael Stutz (Research Assistant) 2011-2013
Publications
Extensive proliferation of human cancer cells with ever-shorter telomeres.
Dagg, R. A., Pickett, H. A., Neumann, A. A., Napier, C. E., Henson, J. D., Teber, E. T., Arthur J. W., Reynolds, C. P., Murray, J., Haber, M., Sobinoff A. P., Lau, L. M. S., Reddel, R. R., 2017. Cell Reports, 19, 2544-2556. PMID: 28636942.
Functional dissection of breast cancer risk-associated TERT promoter variants.
Helbig, S., Wockner, L., Bouendeu, A., Hille-Betz, U., McCue, K., French, J. D., Edwards, S. L., Pickett, H. A., Reddel, R. R., Chenevix-Trench, G., Dork, T., Beesley, J., 2017. Oncotarget, doi: 10.18632/oncotarget.18226. PMID: 28615534.
Whole-genome landscapes of major melanoma subtypes.
Hayward, N. K., Wilmott, J. S., Waddell, N., Johansson, P. A., Field, M. A., Nones, K., Patch, A., Kakavand, H., Alexandrov, L. B., Burke, H., Jakrot, V., Kazakoff, S., Holmes, O., Leonard, C., Sabarinathan, R., Mularoni, L., Wood, S., Xu, Q., Waddell, N., Tembe, V., Pupo, G. M., De Paoli-Iseppi, R., Vilain, R. E., Shang, P., Lau, L. M. S., Dagg, R. A., Schramm, S., Pritchard, A., Dutton-Regester, K., Newell, F., Fitzgerald, A., Shang, C. A., Grimmond, S. M., Pickett, H. A., Yang, J. Y., Stretch, J. R., Behren, A., Kefford, R. F., Hersey, P., Long, G. V., Cebon, J., Shackleton, M., Spillane, A. J., Saw, R. P. M., Bigas, N. L., Pearson, J. V., Thompson, J. F., Scolyer, R. A., Mann, G. J., 2017. Nature, 545, 175-180. PMID: 28467829.
Whole-genome landscape of pancreatic neuroendocrine tumours.
Scarpa, A., Chang, D. K., Nones, K., Corbo, V., Patch, A., Bailey, P., Lawlor, R. T., Johns, A. L., Miller, D. K., Mafficini, A., Rusev, B., Scardoni, M., Antonello, D., Barbi, S., Sikora, K. O., Cingarlini, S., Vicentini, C., McKay, S., Quinn, M. C., Bruxner, T. J. C., Christ, A. N., Harliwong, I., Idrisoglu, S., McLean, S., Nourse, C., Nourbakhsh, E., Wilson, P. J., Anderson, M. J., Fink, J. L., Newell, F., Waddell, N., Holmes, O., Kazakoff, S. H., Leonard, C., Wood, S., Xu, Q., Nagaraj, S. H., Amato, E., Dalai, I., Bersani, S., Cataldo, I., Dei Tos, A. P., Capelli, P., Davi, M. V., Landoni, L., Malpaga, A., Miotto, M., Whitehall, V., Leggett, B., Harris, J. L., Harris, J., Jones, M. D., Humphris, J., Chantrill, L. A., Chin, V., Nagrial, A. M., Pajic, M., Scarlett, C. J., Pinho, A., Rooman, I., Toon, C., Wu, J., Pinese, M., Cowley, M., Barbour, A., Mawson, A., Humphrey, E. S., Colvin, E. K., Chou, A., Lovell, J. A., Jamieson, N. B., Duthie, F., Gingras, M. C., Fisher, W. E., Dagg, R. A., Lau, L. M., Lee, M., Pickett, H. A., Reddel, R. R., Samra, J. S., Kench, J. G., Merrett, N. D., Epari, K., Nguyen, N. Q., Zeps, N., Falconi, M., Simbolo, M., Butturini, G., Van Buren, G., Partelli, S., Fassan, M., Australian Pancreatic Cancer Genome Initiative, Khanna, K. K., Gill, A. J., Wheeler, D. A., Gibbs, R. A., Musgrove, E. A., Bassi, C., Tortora, G., Pederzoli, P., Pearson, J. V., Waddell, N., Biankin, A. V., Grimmond, S. M., 2017. Nature 543, 65-71. PMID: 28199314.
Comparative analysis of whole genome sequencing-based telomere length measurement techniques.
Lee, M., Napier, C. E., Yang, S. F., Arthur, J. W., Reddel, R. R., Pickett, H. A., 2017. Methods 114, 4-15. PMID: 27565742.
Telomeres and stress: Promising avenues for research in psycho-oncology.
Law, E., Girgis, A., Sylvie L., Levesque, J., Pickett, H. A., 2016. Asia Pac. J. Oncol. Nurs. 3, 137-147. PMID: 27981152.
MYC-driven neuroblastomas are addicted to a telomerase-independent function of dyskerin.
O’Brien, R., Tran, S. L., Maritz, M., Liu, B., Kong, C. F., Purgato, S., Yang, C., Murray, J., Russell, A. J., Flemming, C. L., von Jonquieres, G., Pickett, H. A., London, W. B., Haber, M., Gunaratne, P. H., Norris, M. D., Perrini, G., Fletcher, J. I., MacKenzie, K. L., 2016. Cancer Res. 76, 3604-3617. PMID: 27197171.
Molecular mechanisms of alternative lengthening of telomeres activity and derepression.
Pickett, H. A., Reddel, R. R., 2015. Nat. Struct. Mol. Biol. 22, 875-880. PMID: 26581522.
Histone variant H3.3 provides the heterochromatic H3 lysine 9 trimethylation mark at telomeres.
Udugama, M., Chang, F. T. M., Chan, F. L., Tang, M., Pickett, H. A., McGhie, J. D. R., Mayne, L., Collas, P., Mann, J. R., Wong, L. H., 2015. Nucleic Acids Res. 43, 10227-10237. PMID: 26304540.
A common risk-associated allele in the hTERT locus encodes a dominant negative inhibitor of telomerase.
Killedar, A., Stutz, M. D., Sobinoff, A. P., Tomlinson, C. G., Bryan, T. M., Beesley, J., Chenevix-Trench, G., Reddel, R. R., Pickett, H. A., 2015. PLOS Genet. 11 (6):e1005286. PMID: 26053551.
Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1.
Guo, Y., Kartawinata, M., Li, J., Pickett, H. A., Teo, J., Kilo, T., Barbaro, P. M., Keating, B., Chen, Y., Tian, L., Al-Odaib, A., Reddel, R. R., Christodoulou, J., Xu, X., Hakonarson, H., Bryan, T. M., 2014. Blood 2014-08-596445. PMID: 25205116.
NuRD-ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination.
Conomos, D., Reddel, R. R., Pickett, H. A., 2014. Nat. Struct. Mol. Biol. 21, 760-770. PMID:25150861.
Folate deficiency induces dysfunctional long and short telomeres; both states are associated with hypomethylation and DNA damage in human WIL2-NS cells.
Bull, C. F., Mayrhofer, G., O’Callaghan, N. J., Au, A. Y., Pickett, H. A., Kah Mun Low, G., Zeegers, D., Hande, M. P., Fenech, M. F., 2013. Cancer Prev. Res. 7, 128-138. PMID: 24253316.
Telomere extension by telomerase and ALT generates variant repeats by mechanistically distinct processes.
Lee, M., Hills, M., Conomos, D., Stutz, M. D., Dagg, R. A., Lau, L. M. S., Reddel, R. R., Pickett, H. A., 2013. Nucleic Acids Res. 2014 Feb;42(3):1733-46. doi: 10.1093/nar/gkt1117. Epub 2013 Nov 12.. PMID: 24225324.
The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak.
Kojima, Y., Kaufman-Francis, K., Studdert, J. B., Steiner, K. A., Power, M. D., Loebel, D. A. F., Jones, V., Hor, A., de Alencastro, G., Logan, G., Teber, E. T., Tam, O. H., Stutz, M. D., Alexander, I. E., Pickett, H. A., Tam, P. P. L., 2013. Cell Stem Cell 14, 107-120. PMID: 24139757.
Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
Bojesen, S. E., Pooley, K. A., Johnatty, S. E., Beesley, J., Michailidou, K., Tyrer, J. P., Edwards, S. L., Pickett, H. A., Shen, H. C., Smart, C. E., Hillman, K. M., Mai, P. L., Lawrenson, K., Stutz, M. D., Yu, L., Karevan, R., Woods, N., Johnston, R. L., French, J. D., Chen, X., Weischer, M., Nielsen, S. F., Maranian, M.J., Ghoussaini, M., Ahmed, S., et al., 2013. Nat. Genet. 45, 371-384. PMID: 23535731.
Alternative lengthening of telomeres: remodeling the telomere architecture.
Conomos, D., Pickett, H. A., Reddel, R. R., 2013. Front. Oncol. 3:27. doi: 10.3389/fonc.2013.00027. PMID: 23429284.
Alternative lengthening of telomeres in normal mammalian somatic cells.
Neumann, A. A., Watson, C. M., Noble, J. R., Pickett, H. A., Tam, P. T., Reddel, R. R., 2013. Genes Dev. 27, 18-23. PMID: 23307865.
Variant repeats are interspersed throughout the telomeres and recruit nuclear receptors in ALT cells.
Conomos, D., Stutz, M. D., Hills, M., Neumann, A. A., Bryan, T. M., Reddel, R. R., Pickett, H. A., 2012. J. Cell Biol. 199, 893-906. PMID: 23229897.
Normal mammalian cells negatively regulate telomere length by telomere trimming.
Pickett, H. A., Henson, J. D., Au, A. Y. M., Neumann, A. A., Reddel, R. R., 2011. Hum. Mol. Gen. 20, 4684-4692. PMID: 21903669.
Control of telomere length by a trimming mechanism that involves generation of t-circles.
Pickett, H. A., Cesare, A. J., Johnston, R. L., Neumann, A. A., Reddel, R. R., 2009. EMBO J. 28, 799-809. PMID: 19214183.
Molecular characterisation of inter-telomere and intra-telomere mutations in human ALT cells.
Varley, H., Pickett, H. A., Foxon, J. L., Reddel, R. R., Royle, N. J., 2002. Nat. Genet. 30, 301-305. PMID: 11919561
Major Achievements
2009
Identified a novel telomere length control mechanism termed “telomere trimming”, in which homologous recombination-mediated rapid telomere deletion prevents the persistence of overlengthened telomeres.
2011
Characterised regulated telomere trimming in normal human cells of both germline and somatic origin, demonstrating that telomere trimming is a third mechanism of telomere length control.
2012
Demonstrated variant repeat interspersion throughout ALT telomeres as the result of homologous recombination-mediated telomere replication. This results in diminished shelterin binding, sequence-specific nuclear receptor binding, and an altered nucleoprotein structure.
2013
Characterised multiple independent single nucleotide polymorphisms in the TERT locus that associate with breast and ovarian cancer. This study provides definitive evidence for genetic control of telomere length by common genetic variants.
2013
Defined telomere variant repeat content and telomere maintenance mechanism-specific variant repeat generation in human cells. This study demonstrates a conserved role for variant sequences at human telomeres.
2014
Identified recruitment of the NuRD-ZNF827 chromatin remodelling complex specifically to telomeres in cells that use ALT. This study demonstrates a critically important multifaceted role for NuRD-ZNF827 at ALT telomeres.