CHROMOSOME END PROTECTION BY TELOMERES
Jacqueline J.L. Jacobs,
Position: Junior group leader (assistant professor)
Phone: +31 20 512 1784
Linear eukaryotic chromosomes pose several challenges to cells that are a threat to genome integrity. As conventional DNA polymerases cannot replicate the very ends of chromosomes, each time a cell divides in two a bit of DNA sequence is lost from the tips of chromosomes, which could lead to loss of genetic information. Furthermore, cells contain multiple DNA repair activities that act on exposed DNA ends to fix chromosome-internal DNA breaks and prevent unequal separation of genetic information into daughter cells. However, such repair activities acting on natural chromosome ends lead to chromosome end-to-end joining which cause genomic instability when such cells with fused chromosomes go through cell division. To avoid these problems natural chromosome ends are capped by specialized nucleoprotein structures called telomeres.
Telomeres consist of tandem TTAGGG DNA repeats bound by a complex of telomere-specific proteins that control the length and function of telomeres. Telomeres provide a buffer, such that terminal sequence loss will not immediately affect juxtaposed genes. Moreover, telomeres protect natural chromosome ends from being seen and treated as damaged DNA.
In somatic cells with no or little telomerase, the enzyme that can add TTAGGG repeats to telomere ends, telomeres progressively shorten with every cell division until they become too short to function properly. Loss of telomere function triggers a DNA damage-like checkpoint response that results in apoptotic cell death or a permanent growth arrest termed senescence. This response limits the replicative life span of cells and thereby contributes to organismal aging. In addition, the telomere damage response eliminates potentially cancerous cells and represents an important tumor suppressor mechanism. On the other hand dysfunctional telomeres are subject to DNA repair activities that, especially in DNA-damage checkpoint deficient cells, can lead to a degree of genomic instability that promotes the development of cancer.
Our main research interest is in understanding how telomeres protect chromosome ends and what exactly happens when telomere protection is lost.
Hereto we investigate:
the precise nature of the telomere damage signal and how it is sensed and transmitted to the cell cycle machinery to induce senescence;
the cellular activities that act on unprotected chromosome ends and contribute to telomere induced genome instability;
the mechanism by which telomeres protect chromosome ends from activating DNA damage responses and repair activities;
novel factors regulating telomere function or maintenance.
Much is unknown about these issues, however they are very important to address as telomere function affects tumor development and aging, and is targeted by several recently developed anti-cancer strategies that are in clinical testing phases.To address these issues we take both candidate-driven approaches as well as different genome-wide approaches, such as unbiased functional genetic screening. Central in several of these approaches is inhibition of the telomere binding protein TRF2 which allows us to disrupt telomere function at will in a relatively synchronous fashion and to experimentally mimic the consequences of replicative telomere shortening in the absence of extensive culture stress.
Current lab members
Jacqueline Jacobs studied (Medical) Biology at the University of Nijmegen and received her Masters degree in 1996 (cum laude). She performed her PhD studies at the Division of Molecular Carcinogenesis of the Netherlands Cancer Institute with Dr. Maarten van Lohuizen. Here she investigated the underlying basis for the oncogenic activity of the Polycomb-group repressor Bmi1 and got introduced to the senescence tumor suppression mechanism when she identified the INK4a/ARF tumor suppressor locus as an important target for Pc-G repression by Bmi1. Subsequently she developed in vitro genome-wide functional screens to identify novel suppressors of senescence and identified TBX2 as a novel direct repressor of ARF that is amplified in human breast cancer. For the discoveries she made during her PhD she was awarded the Antoni van Leeuwenhoek Award 1999. In 2000 she received her PhD degree (cum laude) from the University of Utrecht. Until the end of 2001 she continued working on the senescence checkpoint as a postdoc at the Netherlands Cancer Institute with Dr. Maarten van Lohuizen. Next to further characterizing the role of Bmi1 and TBX2 in senescence and transformation, she developed in vitro transformation screens to identify novel genes and pathways that collaborate with Myc or Ras oncogenes to promote anchorage-independent growth. From Jan. 2002-June 2004 she was a Dutch Cancer Society postdoctoral fellow with Prof. Dr. Titia de Lange at the Rockefeller University of New York, USA, where she studied telomere function and telomere dysfunction-induced senescence. Since July 2004 she is back at the Netherlands Cancer Institute where in February 2006 she was appointed as research associate/project leader and since June 2008 as junior group leader. Her group investigates the cellular response to loss of telomere function and aims to identify novel components of the telomere damage response and novel regulators of telomere function and telomere maintenance.
- Jacobs, J.L.L. Fusing telomeres with RNF8. Nucleus. 3, 143-149 (2012).
- Peuscher, M.H. and Jacobs, J.L.L. Posttranslational control of telomere maintenance and the telomere damage response. Cell Cycle. 11, 1524-1534 (2012).
- Peuscher, M.H. and Jacobs, J.L.L. DNA-damage response and repair activities at uncapped telomeres depend on RNF8. Nature Cell Biol. 13, 1139-1145 (2011).
- Taghavi, P., Verhoeven, E., Jacobs, J.J.L., Lambooij, J-P., Stortelers, C., Tanger, E., Moolenaar, W.H. and van Lohuizen, M. In Vitro Genetic Screen Identifies a Cooperative Role for LPA Signaling and c-Myc in Cell Transformation. Oncogene 27, 6806-6816 (2008).
- Jacobs, J.J.L, and de Lange, T. p16INK4a as a Second Effector of the Telomere Damage Pathway. Cell Cycle 4, 1364-1368 (2005).
- Bruggeman, S.W.*, Valk-Lingbeek, M.E.*, van der Stoop, P.P.*, Jacobs, J.J.L*, Kieboom, K., Tanger, E., Hulsman, D., Leung, C., Arsenijevic, Y., Marino, S., and van Lohuizen, M. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev 19, 1438-1443 (2005).
- Jacobs, J.J.L. and de Lange, T. Significant role for p16INK4a in p53-independent telomere-directed senescence. Current Biol. 14: 2302-2308 (2004).
- Itahana, K., Zou, Y., Itahana, Y., Martinez, J.-L., Beausejour, C., Jacobs, J.J.L., van Lohuizen, M., Band, V., Campisi, J., Dimri, G.P. Control of the replicative life span of human fibroblasts by p16 and the Polycomb protein Bmi-1. Mol. Cell. Biol. 23: 389-401 (2003).
- Dimri, G.P., Martinez, J.-L., Jacobs, J.J.L., Keblusek, P., Itahana, K., van Lohuizen, M., Campisi, J., Wazer, D.E., Band, V. The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res. 62: 4736-4745 (2002).
- Jacobs, J.J.L., van Lohuizen, M. Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim Biophys Acta 1602: 151-161 (2002).
- Lingbeek, M.E., Jacobs, J.J.L., van Lohuizen, M. The T-box repressors TBX2 and TBX3 specifically regulate the tumor-suppressor p14ARF via a variant T-site in the initiator. J. Biol. Chem. 29: 26120-26127 (2002).
- Jacobs, J.J.L., Keblusek, K., Robanus-Maandag, E., Kristel, P., Lingbeek, M., Nederlof, P.M., van Welsem, T., van de Vijver, M.J., Koh, E.Y., Daley, G.Q., van Lohuizen, M. Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19ARF) and is amplified in a subset of human breast cancers. Nature Genetics 26: 291-299 (2000).
- Jacobs, J.J.L. Control of cell proliferation and senescence by the Polycomb-group gene Bmi1. Dissertation University of Utrecht, ISBN 90-393-23777-1 (2000).
- Jacobs, J.J.L., Scheijen B., Voncken, J.W., Kieboom, K., Berns, A., van Lohuizen, M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc induced apoptosis via INK4a/ARF. Genes & Development 13: 2678-2690 (1999).
- Jacobs, J.J.L. and van Lohuizen, M. Cellular memory of transcriptional states by Polycomb-group proteins. Seminars in Cell and Developmental Biology 10 (2): 227-235 (1999).
- Jacobs, J.J.L., Kieboom, K., Marino, S., DePinho, R.A., van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397: 164-168 (1999).
- Alkema, M.J., Jacobs, J., Voncken J.W., Jenkins, N.A., Copeland, N.G., Satijn, D.P.E., Otte, A.P., Berns, A. and van Lohuizen, M. MPc2, a new murine homolog of the Drosophila Polycomb protein is a member of the mouse Polycomb transcriptional repressor complex. Journal of Molecular Biology 273: 993-1003 (1997).