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Oncogenomics: Jacqueline Jacobs

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Jacqueline Jacobs, Ph.D.Group Leader

About 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 (summer/autumn 2020)
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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Zainab Tayeh

Zainab Tayeh

Postdoctoral Fellow

Experience

I obtained my doctoral thesis studies in the laboratory of  "DNA replicative stress in cancer "under the supervision of Prof. Dr. med. Matthias Dobbelstein, at Institute of Molecular Oncology of University of Göttingen (Göttingen, Germany). My Ph.D. thesis mainly focused on the understanding of how centrosome integrity can affect DNA replication independently from mitosis and chromosomal missegregation. As the manuscript of my thesis is still under revision by the official journal, an online version of it was published as a preprint at BioRxiv. The manuscript reveals a novel connection between centrosomes integrity and DNA replication apart from mitotic insults through the formation of secondary structures called R-loops upon the activation of the MLK3-P38-MK2 pathway. In March 2020 I started in the lab of Jaqueline Jacobs as a postdoc, where I aim to better understand the mechanisms behind overcoming replication challenges at telomeres.

 

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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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Lance Lam

Lance Lam

Ph.D. student

Experience

I am Lance Lam. I came from Hong Kong. I obtained my Bachelor and Master degrees at the University of Hong Kong. I worked on the functional characterization of novel cancer predisposition genes/mutations in the context of esophageal cancer for my Bachelor and master project. I joined the Jacobs Lab in 2020 as a PhD student to study ubiquitination and telomere damage response.  

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Alexander Thouin

Alexander Thouin

Ph.D. student

Experience

I completed my BSc (hons) in biomedical science at the University of Bath (UK), after which I undertook a research MSc at the Rijksuniversiteit Groningen (NL). During my masters, I did an internship with prof. dr. Arjan Kortholt in the biochemistry department investigating LRRK2 signaling in Parkinson's disease. My second internship was in the lab of prof. dr. Marcel van Vugt at the University Medical Center Groningen (UMCG). There I worked on DNA-damage response pathways related to cancer therapy. Currently, at the NKI, I will investigate the mechanisms of DNA repair at double-stranded breaks and de-protected telomeres. 

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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 Dutch Cancer Foundation (KWF, call 2019-2)

    Jacqueline Jacobs received a grant from the Dutch Cancer Foundation (KWF, call 2019-2) to explore novel modes of DNA repair control by ubiquitin(-like) reversal.

  • 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

  • H3K36 Dimethylation by MMSET Promotes Classical Non-Homologous End-Joining at Unprotected Telomeres

    (2020) Oncogene

    Inge de Krijger, Jaco van der Torre, Marieke H Peuscher, Mathias Eder, Jacqueline J L Jacobs

    Link to Nature
  • 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
 

Contact

  • Office manager

    Elise Marseille

  • E-mail

    e.marseille@nki.nl

  • Telephone Number

    +31 20 512 2015

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