Alternative Lengthening of Telomeres

 Telomeres are present at the ends of chromosomes and consist of tandem 5’-TTAGGG-3’ repeats. These form structures that maintain genome stability by protecting DNA ends from degradation or fusing with other chromosomes.  Replication of chromosomes does not continue to their ends, so the telomere is slightly shortened during each round of replication.  In somatic cells, which have no means of lengthening their telomeres, this means the number of times a cell can divide is limited.

For cancer cells to have unlimited replicative potential, the replicative limit placed on cells by telomere attrition, or Hayflick limit, must be overcome. There are two main ways in which this is achieved.  Often cells reactivate telomerase.  Telomerase is an enzyme active in stem cells and uses an RNA template to synthesise telomeric DNA so reactivation allows telomeres to be regenerated and replication to continue.  The second route to overcoming the Hayflick limit is known as Alternative Lengthening of Telomeres, or ALT.  This is defined as lengthening mechanisms that do not rely on telomerase (Pickett and Reddel 2015).

Alternative Lengthening of Telomeres is proposed to take place via a mechanism whereby another telomere is used as a DNA template for replication of new telomeric DNA. Telomeric DNA ends are thought to invade a homologous template ( Figure 1, Step 1) and undergo synthesis (Step 2) before the recombination intermediate formed is resolved (Step 3).

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Figure 1 from Pickett and Reddel 2015.

This process involves proteins central to DNA replication and recombination and seems to be prevented in normal cells by telomere binding proteins such as POT1 and also by chromatin structure.

Since the ALT process has been estimated to occur in 10-15% of cancers, including some with high mortality rates, it is obviously of therapeutic interest (Cesare and Reddel 2010, Scarpa, Chang et al. 2017).   However, the involvement of components of recombination and replication machinery in this process is not completely defined.

A recent paper (Dilley, Verma et al. 2016) has defined the molecular requirements for ALT using an assay that induces damage specifically at telomeres and then observes DNA incorporation into telomeres.

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Figure 2 from Dilley, Verma et al. 2016.

  1. Telomere specific damage is induced by using a restriction endonuclease fused to Telomere Repeat-binding Factor 1
  2. The nucleoside analogue BrdU labels newly synthesised DNA

3-5  DNA is fragmented and that containing newly synthesised DNA is separated from the bulk DNA

  1. Probing for telomeres allows newly synthesised telomeres to be quantified.

This system monitors break induced replication at telomeres. By combining this system with siRNA the group were able to define the requirements for break induced replication at telomeres and determine several replication factors involved in the process.  They demonstrated that for this process, ATR and Rad51 were not required, and that replication factor C, proliferating cell nuclear antigen and DNA polymerase δ. Identification of how this process differs from S-phase replication may provide novel targets for therapeutics.

Blog written by Jess Hudson


Cesare, A. J. and R. R. Reddel (2010). “Alternative lengthening of telomeres: models, mechanisms and implications.” Nat Rev Genet 11(5): 319-330.

Dilley, R. L., P. Verma, N. W. Cho, H. D. Winters, A. R. Wondisford and R. A. Greenberg (2016). “Break-induced telomere synthesis underlies alternative telomere maintenance.” Nature 539(7627): 54-58.

Pickett, H. A. and R. R. Reddel (2015). “Molecular mechanisms of activity and derepression of alternative lengthening of telomeres.” Nat Struct Mol Biol 22(11): 875-880.

Scarpa, A., D. K. Chang, K. Nones, V. Corbo, A.-M. Patch, P. Bailey, R. T. Lawlor, A. L. Johns, D. K. Miller, A. Mafficini, B. Rusev, M. Scardoni, D. Antonello, S. Barbi, K. O. Sikora, S. Cingarlini, C. Vicentini, S. McKay, M. C. J. Quinn, T. J. C. Bruxner, A. N. Christ, I. Harliwong, S. Idrisoglu, S. McLean, C. Nourse, E. Nourbakhsh, P. J. Wilson, M. J. Anderson, J. L. Fink, F. Newell, N. Waddell, O. Holmes, S. H. Kazakoff, C. Leonard, S. Wood, Q. Xu, S. H. Nagaraj, E. Amato, I. Dalai, S. Bersani, I. Cataldo, A. P. Dei Tos, P. Capelli, M. V. Davì, L. Landoni, A. Malpaga, M. Miotto, V. L. J. Whitehall, B. A. Leggett, J. L. Harris, J. Harris, M. D. Jones, J. Humphris, L. A. Chantrill, V. Chin, A. M. Nagrial, M. Pajic, C. J. Scarlett, A. Pinho, I. Rooman, C. Toon, J. Wu, M. Pinese, M. Cowley, A. Barbour, A. Mawson, E. S. Humphrey, E. K. Colvin, A. Chou, J. A. Lovell, N. B. Jamieson, F. Duthie, M.-C. Gingras, W. E. Fisher, R. A. Dagg, L. M. S. Lau, M. Lee, H. A. Pickett, R. R. Reddel, J. S. Samra, J. G. Kench, N. D. Merrett, K. Epari, N. Q. Nguyen, N. Zeps, M. Falconi, M. Simbolo, G. Butturini, G. Van Buren, S. Partelli, M. Fassan, I. Australian Pancreatic Cancer Genome, K. K. Khanna, A. J. Gill, D. A. Wheeler, R. A. Gibbs, E. A. Musgrove, C. Bassi, G. Tortora, P. Pederzoli, J. V. Pearson, N. Waddell, A. V. Biankin and S. M. Grimmond (2017). “Whole-genome landscape of pancreatic neuroendocrine tumours.” Nature 543(7643): 65-71.


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