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Oncogenomics: 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.

Positions available (autumn 2019)
We regularly have Postdoc, PhD student, Technician and Master student positions available. If you are interested in joining our lab, please send an enquiring email including your CV and motivation to Jacqueline Jacobs (j.jacobs@nki.nl).

 

 

Co-workers

Hernandez Perez S

Santiago Hernandez Perez

Postdoctoral Fellow

Experience

I undertook my doctoral thesis studies in the laboratory of "Response to DNA Damage and Cancer" directed by Dr. Raimundo Freire Betancor at La Laguna University (Tenerife, Spain), where I focused on the understanding of the DNA replication control by post-translational modifications. This thesis is a published work in which I have identified USP7 and DUB3, and USP37 as ubiquitin hydrolases that control the protein levels of Geminin and Cdt1 respectively. Moreover, I have shown that the expression of USP7 strongly correlates with the expression of Geminin in breast cancer, and that low or high levels of USP7 are associated with poor prognosis. In addition, I have identified a novel role of PERK in DNA replication control. I showed that suppression of DNA replication by the unfolding protein response after endoplasmic reticulum stress occurs via PERK acting through Claspin and Chk1 downstream. In addition, during my PhD I worked some months in the laboratory of "Functional Organization and Plasticity of Mammalian Genomes" supervised by Dr. Michelle Debatisse in the Institute Curie (Paris, France) to learn DNA combing.

In August 2019 I started in the lab of Jaqueline Jacobs as a postdoc, where I aim to better understand the role of the ubiquitin hydrolases controlling DNA damage response. 

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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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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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Paniagua Cabana, Inés

Inés Paniagua Cabana

Ph.D. student

Experience

I have completed a bachelor's degree in Biotechnology at the University of León (Spain) and a master's degree in Biomedical Sciences at the University of Groningen (The Netherlands). During this time, I was trained by Dr. José Luis Fernández-García (COG, Spain), Dr. Michael Chang (ERIBA, The Netherlands), and Prof. Daniel Durocher (LTRI, Canada). All three research projects were carried out in the field of telomere biology and further confirmed my interest in pursuing a PhD in this area. I have now joined the lab of Dr. Jacqueline Jacobs to study the mechanisms underlying telomere replication and maintenance and the consequences of telomere replication stress.

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Research updates View All Updates

  • Grant from the EU (EU H2020-MSCA-ITN-2018)

    Jacqueline Jacobs received a grant from the EU as participant in the "aDDress" Marie Curie ITN Consortium composed of an international collaboration between 11 academic and 3 non-academic participants with focus on chromatin dynamics, DNA damage signalling, repair mechanisms and their impact on development and disease.

  • Grant from the Dutch Cancer Foundation (KWF, call 2018-2)

    Jacqueline Jacobs received a grant from the Dutch Cancer Foundation (KWF, call 2018-2) to explore the mechanisms to overcome replication challenges at telomeres.

Key publications View All Publications

  • MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5' end resection

    (2015) Nature

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

    Link to PubMed
  • 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
 
 

Recent publications View All Publications

  • Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells

    (2018) Nature Cell Biology

    Dev H, Chiang TW, Lescale C, de Krijger I, Martin AG, Pilger D, Coates J, Sczaniecka-Clift M, Wei W, Ostermaier M, Herzog M, Lam J, Shea A, Demir M, Wu Q, Yang F, Fu B, Lai Z, Balmus G, Belotserkovskaya R, Serra V, O'Connor MJ, Bruna A, Beli P, Pellegrini L, Caldas C, Deriano L*, Jacobs JJL*, Galanty Y*, Jackson SP*.

    *corresponding authors

     

    Link to PubMed
  • The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells

    (2018) Cell Reports

    Barazas M, Annunziato S, Pettitt SJ, de Krijger I, Ghezraoui
    H, Roobol SJ, Lutz C, Frankum J, Song FF, Brough R, Evers B, Gogola E, Bhin J,
    van de Ven M, van Gent DC, Jacobs JJL, Chapman R, Lord CJ, Jonkers J,
    Rottenberg S
    .

    Link to PubMed
 

Contact

  • Office manager

    Elise Marseille

  • E-mail

    e.marseille@nki.nl

  • Telephone Number

    +31 20 512 2015

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