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Molecular Oncology: Jacqueline Jacobs

Telomere Damage and Cancer

Research interest

Natural chromosome ends are capped by specialized nucleoprotein structures called telomeres. Telomeres are essential for the maintenance of genome integrity by protecting natural chromosome ends from being seen and treated as broken DNA ends. Telomeres consist of tandem TTAGGG DNA repeat sequences bound by the 'shelterin' complex of telomere-specific proteins that control the length and end-protection function of telomeres. Chromosome ends can lose telomere protection when telomeres become critically short as a consequence of multiple rounds of cell division and when the activity of shelterin components is lost.

When telomeres become dysfunctional they limit the replicative lifespan of a cell by activating a DNA damage response that forces it into a senescent state or to undergo cell death (apoptosis). While these both contribute to the aging process, they also act as a mechanism to inhibit cancer development by limiting the outgrowth of incipient cancer cells. However, if the cell escapes senescence or death and divides, misplaced DNA repair at chromosome ends causes end-to-end chromosomal fusions that can lead to extensive genome instability and ultimately to cancer.

The aim of our work is to understand the molecular mechanisms that underlie these responses to telomere dysfunction and that have critical consequences for cancer development and aging. To do this, we take both unbiased and candidate-driven approaches, alongside in-depth mechanistic studies, particularly focused on identifying what precise DNA damage signaling responses and processing activities act at telomeres and how these are regulated.

We are utilizing genetic screens and proteomics-based approaches to identify proteins and post-translational modifications with critical roles in the cellular response to unprotected telomeres. We use well-controllable models such as the fast and reversible temperature-dependent inactivation of the telomere-capping protein TRF2, which allows us to investigate both immediate and late events associated with the activation of DNA damage responses at telomeres. These models also allow us to address how DNA damage responses are inhibited or terminated. Through subsequent functional studies on the newly identified factors and pathways, we aim to generate a comprehensive understanding of the mechanisms underlying telomere-dependent control of cancer development and aging.

Co-workers

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Vera Boersma

Ph.D. student

Experience

After my Bachelor Biomedical sciences I took part in the Master's program Cancer Genomics and Developmental Biology at the University of Utrecht.

For my first research project during my Master's I worked on cardiac development in zebrafish in the group of Dr. Jeroen Bakkers at the Hubrecht Institute. My second research project was at the Netherlands Cancer Institute in the group of Dr. Jacqueline Jacobs on the telomere damage response.

In October 2012 I joined the lab of Dr. Jacqueline Jacobs as a PhD student to continue my research on the DNA damage response as a result of telomere dysfunction.

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Inge de Krijger

Ph.D. student

Experience

After finishing my bachelor in Molecular Life Science I studied at the University of Vermont for one semester and continued with my Masters in Molecular Life Science at the Radboud University in Nijmegen. During my master I did two research internships, starting at the Department of Pathology at the Radboud UMC Nijmegen where I worked on microRNAs. My second internship was performed at the Signal Transduction Laboratory of Julian Downward in the London Research Institute, working on PI3K signaling. In november I started in the lab of Jacqueline Jacobs focusing on the role of methylation in the telomere damage response.

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Marco Simonetta

Postdoctoral Fellow

Experience

I obtained my PhD in Dr. Andrea Musacchio's lab at the European Institute of Oncology in Milan, where I studied the autocatalytic mechanism and kinetics of Mad2 activation in vitro, which is required to sustain the mitotic checkpoint signaling during metaphase.
From 2009 to 2012, I worked in Dr. David Toczyski's lab at UCSF, where, using yeast as model, I developed a Ligase Trapping technology, which allowed the identification of novel ubiquitination substrates by LC-MS/MS analysis.
In Dr. Jacqueline Jacobs' lab, my aim is to perform a genome-wide screen for telomere regulators and study their possible roles in human cancer.

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Zeliha Yalcin

Ph.D. student

Experience

I am Zeliha and I did a Master in Biomolecular Sciences at the Vrije Universiteit (VU) in Amsterdam. My first internship was at the Netherlands Cancer Institute (NKI) in the group of Huib Ovaa, where I characterized and inhibited deubiquitinating enzymes in Trypanosoma brucei. My second internship was at the Leiden University Medical Center in the group of Marjolein Kikkert, where I studied the function of conserved cysteines in Equine arteritis virus non-structural protein 2.

In December 2012, I joined the lab of Jacqueline Jacobs as a PhD student, where I work on ubiquitination in the telomere damage response.

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Serrat, Judit

Judit Serrat

Technician

Experience

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Research updates View All Updates

  • PhD fellowship from Boehringer Ingelheim Fonds

    Inge de Krijger was awarded a highly competitive PhD fellowship from Boehringer Ingelheim Fonds. Starting October 1st, 2013 this fellowship will support 2 years of her PhD studies on the role of methylation in the telomere damage response.

  • We are looking for highly motivated and talented postdocs to join us. Please check our vacancies web page or directly email Jacqueline Jacobs with your motivation letter, CV, list of publications and contact details of at least 2 referees.

Key publications View All Publications

  • DNA-damage response and repair activities at uncapped telomeres depend on RNF8

    Nat Cell Biol. 2011; 13: 1139-45

    Peuscher MH, Jacobs JJ.

    link to PubMed
  • MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5' end resection.

    Nature. 2015 May 28

    Boersma V, Moatti N, Segura-Bayona S, Peuscher MH, van der Torre J, Wevers BA, Orthwein A, Durocher D, Jacobs JJ.

    Link to PubMed
 
 

Recent publications View All Publications

  • PARP1 Links CHD2-Mediated Chromatin Expansion and H3.3 Deposition to DNA Repair by Non-homologous End-Joining.

    Mol Cell. 2016 Feb 18

    Luijsterburg MS, de Krijger I, Wiegant WW, Shah RG, Smeenk G, de Groot AJ, Pines A, Vertegaal AC, Jacobs JJ, Shah GM, van Attikum H.

    link to PubMed
  • Loss of telomere protection: consequences and opportunities

    Front Oncol. 2013; 3: 88

    Jacobs, JJ

    link to PubMed
 

Contact

  • Office manager

    Karin Hageman

  • E-mail

    k.hageman@nki.nl

  • Telephone Number

    +31 20 512 2099

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