Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Telomere lengthening early in development


Stem cells and cancer cells maintain telomere length mostly through telomerase1,2,3. Telomerase activity is high in male germ line and stem cells, but is low or absent in mature oocytes and cleavage stage embryos, and then high again in blastocysts3. How early embryos reset telomere length remains poorly understood. Here, we show that oocytes actually have shorter telomeres than somatic cells, but their telomeres lengthen remarkably during early cleavage development. Moreover, parthenogenetically activated oocytes also lengthen their telomeres, thus the capacity to elongate telomeres must reside within oocytes themselves. Notably, telomeres also elongate in the early cleavage embryos of telomerase-null mice, demonstrating that telomerase is unlikely to be responsible for the abrupt lengthening of telomeres in these cells. Coincident with telomere lengthening, extensive telomere sister-chromatid exchange (T-SCE) and colocalization of the DNA recombination proteins Rad50 and TRF1 were observed in early cleavage embryos. Both T-SCE and DNA recombination proteins decrease in blastocyst stage embryos, whereas telomerase activity increases and telomeres elongate only slowly. We suggest that telomeres lengthen during the early cleavage cycles following fertilization through a recombination-based mechanism, and that from the blastocyst stage onwards, telomerase only maintains the telomere length established by this alternative mechanism.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Telomere lengthening in one- to two-cell embryos.
Figure 2: Telomerase-independent telomere elongation in one-to two-cell embryos.
Figure 3: T-SCE in early cleavage embryos revealed by CO-FISH.
Figure 4: Expression and localization of Rad50 in early cleavage embryos.


  1. 1

    Allsopp, R. C. et al. Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl Acad. Sci. USA 89, 10114–10118 (1992).

    CAS  Article  Google Scholar 

  2. 2

    Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).

    CAS  Article  Google Scholar 

  3. 3

    Wright, W. E., Piatyszek, M. A., Rainey, W. E., Byrd, W. & Shay, J. W. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 18, 173–179 (1996).

    CAS  Article  Google Scholar 

  4. 4

    Hande, M. P., Samper, E., Lansdorp, P. & Blasco, M. A. Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J. Cell Biol. 144, 589–601 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Prowse, K. R. & Greider, C. W. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc. Natl Acad. Sci. USA 92, 4818–4822 (1995).

    CAS  Article  Google Scholar 

  6. 6

    Poon, S. S., Martens, U. M., Ward, R. K. & Lansdorp, P. M. Telomere length measurements using digital fluorescence microscopy. Cytometry 36, 267–278 (1999).

    CAS  Article  Google Scholar 

  7. 7

    Herrera, E. et al. Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J. 18, 2950–2960 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Hemann, M. T. & Greider, C. W. Wild-derived inbred mouse strains have short telomeres. Nucleic Acids Res. 28, 4474–4478 (2000).

    CAS  Article  Google Scholar 

  9. 9

    Cawthon, R. M. Telomere measurement by quantitative PCR. Nucleic Acids Res. 30, e47 (2002).

    Article  Google Scholar 

  10. 10

    Callicott, R. J. & Womack, J. E. Real-time PCR assay for measurement of mouse telomeres. Comp. Med. 56, 17–22 (2006).

    CAS  PubMed  Google Scholar 

  11. 11

    Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).

    CAS  Article  Google Scholar 

  12. 12

    Schaetzlein, S. et al. Telomere length is reset during early mammalian embryogenesis. Proc. Natl Acad. Sci. USA 101, 8034–8038 (2004).

    CAS  Article  Google Scholar 

  13. 13

    Herrera, E., Martinez, A. C. & Blasco, M. A. Impaired germinal center reaction in mice with short telomeres. EMBO J. 19, 472–481 (2000).

    CAS  Article  Google Scholar 

  14. 14

    Kass-Eisler, A. & Greider, C. W. Recombination in telomere-length maintenance. Trends Biochem. Sci. 25, 200–204 (2000).

    CAS  Article  Google Scholar 

  15. 15

    Bailey, S. M., Brenneman, M. A. & Goodwin, E. H. Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells. Nucleic Acids Res. 32, 3743–3751 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Bechter, O. E., Zou, Y., Walker, W., Wright, W. E. & Shay, J. W. Telomeric recombination in mismatch repair deficient human colon cancer cells after telomerase inhibition. Cancer Res. 64, 3444–3451 (2004).

    CAS  Article  Google Scholar 

  17. 17

    Londono-Vallejo, J. A., Der-Sarkissian, H., Cazes, L., Bacchetti, S. & Reddel, R. R. Alternative lengthening of telomeres is characterized by high rates of telomeric exchange. Cancer Res. 64, 2324–2327 (2004).

    CAS  Article  Google Scholar 

  18. 18

    Gonzalo, S. et al. DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nature Cell Biol. 8, 416–424 (2006).

    CAS  Article  Google Scholar 

  19. 19

    Wang, S. S. & Zakian, V. A. Telomere-telomere recombination provides an express pathway for telomere acquisition. Nature 345, 456–458 (1990).

    CAS  Article  Google Scholar 

  20. 20

    Muntoni, A. & Reddel, R. R. The first molecular details of ALT in human tumor cells. Hum. Mol. Genet. 14, R191–R196 (2005).

    CAS  Article  Google Scholar 

  21. 21

    Bressan, D. A., Baxter, B. K. & Petrini, J. H. The Mre11–Rad50–Xrs2 protein complex facilitates homologous recombination-based double-strand break repair in Saccharomyces cerevisiae. Mol. Cell Biol. 19, 7681–7687 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Stavropoulos, D. J. et al. The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis. Hum. Mol. Genet. 11, 3135–3144 (2002).

    CAS  Article  Google Scholar 

  23. 23

    Lundblad, V. Telomere maintenance without telomerase. Oncogene 21, 522–531 (2002).

    CAS  Article  Google Scholar 

  24. 24

    Zhu, X. D., Kuster, B., Mann, M., Petrini, J. H. & de Lange, T. Cell-cycle-regulated association of RAD50–MRE11–NBS1 with TRF2 and human telomeres. Nature Genet. 25, 347–352 (2000).

    CAS  Article  Google Scholar 

  25. 25

    Hartsuiker, E., Vaessen, E., Carr, A. M. & Kohli, J. Fission yeast Rad50 stimulates sister chromatid recombination and links cohesion with repair. EMBO J. 20, 6660–6671 (2001).

    CAS  Article  Google Scholar 

  26. 26

    Morgan, H. D., Santos, F., Green, K., Dean, W. & Reik, W. Epigenetic reprogramming in mammals. Hum. Mol. Genet. 14, R47–R58 (2005).

    CAS  Article  Google Scholar 

  27. 27

    Tanemura, K. et al. Dynamic rearrangement of telomeres during spermatogenesis in mice. Dev. Biol. 281, 196–207 (2005).

    CAS  Article  Google Scholar 

  28. 28

    Laud, P. R. et al. Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway. Genes Dev. 19, 2560–2570 (2005).

    CAS  Article  Google Scholar 

  29. 29

    Verdun, R. E. & Karlseder, J. The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. Cell 127, 709–720 (2006).

    CAS  Article  Google Scholar 

  30. 30

    Keefe, D. L., Liu, L. & Marquard, K. Telomeres and aging-related meiotic dysfunction in women. Cell Mol. Life Sci. 64, 139–143 (2007).

    CAS  Article  Google Scholar 

  31. 31

    Baird, D. M. et al. Telomere instability in the male germline. Hum. Mol. Genet. 15, 45–51 (2006).

    CAS  Article  Google Scholar 

  32. 32

    Lanza, R. P. et al. Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science 288, 665–669 (2000).

    CAS  Article  Google Scholar 

  33. 33

    Wakayama, T. et al. Cloning of mice to six generations. Nature 407, 318–319 (2000).

    CAS  Article  Google Scholar 

Download references


We thank V. Zakian and J. Petrini for advice on the Rad50 and telomere recombination work, P. Lansdorp for providing TFL telomere-analysis software and advice on Q-FISH analysis, and I. Hickson for providing anti-BLM antibodies. This work was partly supported by the Women and Infants Hospital/Brown Faculty Research (D.L.K. and L.L.), National Nature Science Foundation China (L.L.), James and Esther King Biomedical Research Program (L.L.) and the MCyT, European Union and the Josef Steiner Award 2003 (M.A.B.).

Author information




L.L. and D.L.K. designed the study. L.L., S.M.B., M.O., P.M., C.L., L.Z., C.W., E.C., L.S. and A.S. performed the experiments. M.A.B. provided the TRKO mice and advice. L.L. and D.L.K. wrote the paper, and S.M.B, M.A.B. and A.S. revised the manuscript.

Corresponding authors

Correspondence to Lin Liu or David L. Keefe.

Supplementary information

Supplementary Information

Supplementary figures S1, S2, S3, S4, S5 and S6 (PDF 2315 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liu, L., Bailey, S., Okuka, M. et al. Telomere lengthening early in development. Nat Cell Biol 9, 1436–1441 (2007).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing