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Tumor Biology & Immunology: Heinz Jacobs

Heinz Jacobs.jpg

Heinz Jacobs, Ph.D.Head of Division, Group Leader

About Heinz Jacobs

Research interest

To maintain genetic integrity in a genotoxic microenvironment, effective countermeasures evolved. Research over the past decades revealed the existence and relevance of DNA-damage response (DDR), DNA repair, and DNA-damage tolerance (DDT) pathways in coping with genotoxic stress. At present we can envision these activities as a 'smart' molecular network, licensed to sense DNA damage, adapt the cell cycle, transiently tolerate genotoxic lesions and restore genetic information, or - if the damage is too harmful - force the system to go into growth arrest or trigger apoptosis. The complexity and flexibility of this DNA-damage management network ensures that mutagenic lesions are usually restored efficiently. In this context it appears quite controversial that lymphocytes are licensed to transiently activate specific mutator systems that enable efficient remodeling of genes coding antigen-receptor chains. To generate the enormous diversity of antigen receptors, specific DNA lesions have to be generated and resolved at defined developmental stages. This hallmark of lymphocytes provides an ideal model system to study the role of specific DNA modifiers as well as generic DNA repair and DDT pathways in shaping the Ig gene repertoire and determine their impact on genome stability and lymphoma development.

Research activities in the group of H. Jacobs are focused on two research topics:

Role of programmed mutagenesis in the somatic evolution of cancer
B cells use programmed mutagenesis to diversify immunoglobulin genes. The activation induced cytidine deaminase (AID) triggers this highly mutagenic process by deaminating cytosine in the variable and switch regions of immunoglobulin genes. AID has been implicated in the accumulation of oncogenic mutations including chromosomal translocations. We are trying to understand how these translocations arise downstream of AID.

Decision making
DNA damage can block replication, and lead to mutations, genomic instability and cancer. In cases when the removal of DNA damage and restoration of the original sequence prior to replication is impossible, cell utilize DNA damage tolerance mechanisms, which help replication to bypass the lesions. A major universal tolerance mechanism is TLS, in which specialized low-fidelity DNA polymerases elongate the DNA across the lesion. This is a double-edged sword because the price of completion of replication is the risk of increased point mutations opposite the lesion. Thus, the regulation is critical for in determining mutational or anti-mutational outcome. A key element in TLS regulation is the attachment of ubiquitin to the PCNA protein, a sliding DNA clamp that tethers the DNA polymerases to DNA, which functions to recruit the TLS DNA polymerase to the damaged site in DNA. Using several independent systems we recently demonstrated the existence of PCNA ubiquitination-dependent and -independent TLS activation pathways in mammals.

Mutagenic processing
To establish somatic mutations from DNA lesions induced by AID, B cells take advantage of the unique catalytic activity of error prone TLS DNA polymerase. TLS polymerases are capable of resuming DNA synthesis at or around DNA lesions, albeit often at the expense of accuracy. We are studying recombinant mouse models and cell lines thereof to determine the contribution of individual TLS polymerases, their functional domains and functional redundancy to the mutation process.


Non-coding function of coding IgH transcripts in establishing allelic exclusion
By assembling variable (V), diversity (D), and joining (J) gene segments in immunoglobulin (Ig) heavy (H) and light (L) chain genes precursor B cells generate clonotypic antibodies with diverse antigen specificities. Though potentially each B cell can express two different IgH and six different IgL chains (2κ and 4λ) and hence twelve different antigen specificities, Ig allelic exclusion ensures that B cells are mono-specific and antibody responses antigen-specific. How this critical 'one B cell - one antibody rule' is established is best compatible with the regulated model of allelic exclusion, where the product of the first productively rearranged allele prohibits further rearrangement of the second. While for decades this feedback loop appeared to be controlled at the level of the protein product, our recent findings indicate that a progenitor B cells is capable of sensing and distinguishing a productive from a non-productive rearrangement on the basis of differential mRNA stability. These data argue for a regulatory, non-coding function of coding Igμ transcripts in establishing IgH chain gene allelic exclusion. At present we investigate how stable, coding Igμ transcripts exert their non-coding function regarding the establishment of IgH chain allelic exclusion, a central prerequisite for the effective generation of a self-tolerant B cell repertoire and the suppression of autoimmunity and B cell tumors.

Co-workers

Berk, Paul van den

Paul van den Berk, MSc

Research Technician, Lab Manager

Experience

In November 1989 I started to work at the NKI at the department of Immunology where I worked for several group leaders. Here I specialized in cellular, molecular, and recombinant mouse model techniques. In February 2003 I started as a technician in the group of Dr. Heinz Jacobs. In his group I collaborate with the PhD students and under graduate students. Besides my work as a technician I am the Deputy Lab Manager, Biological Safety Officer and Emergency Response Officer of our division.

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Aslam, Muhammad

Muhammad Assad Aslam, MSc

Ph.D. student

Experience

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Groot

Daniel de Groot

Ph.D. Student

Experience

As an undergraduate, I worked with Bauke Ylstra at the CCA to ascertain clonality of tumours using CNV analysis. For my Oncology Master's programme at the VU, I performed my first internship at the Borst group (NKI) wherein I worked on lymphoid precursors. I pursued my Master's thesis project with the Birsoy group at the Rockefeller, New York. Here, I elucidated the relation between metabolism and oxidative stress in cancer.

In October 2017, I joined the group of Heinz Jacobs for my PhD working on the pro- and anti-mutagenic activities of TLS polymerases and their contribution to the molecular network controlling DNA damage response.

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Experience

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Shah

Ronak Shah

Ph.D. Student

Experience

I completed my Master's in Biomedical Sciences from University of Amsterdam in 2017. My first internship was in the van Tellingen group at NKI, where I worked on radiosensitization of glioblastomas using targeted therapy. My second internship was in the Ktistakis group, Cambridge, wherein I contributed to delineating the signaling process involved in mitophagy.

In the Jacobs group, I'm interested in understanding the role of the DNA Damage Tolerance (DDT) in stem cell maintenance and tissue homeostasis. I utilize organoids and mouse models to determine the behavior of stem cells in DDT-deficient conditions.

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Spanjaard

Aldo Spanjaard, Msc

Ph.D. Student

Experience

I studied biomedical sciences at the University of Amsterdam. I performed my master internship in the group of Jannie Borst, Division of Immunology, Netherlands Cancer Institute, Ansterdam. Since March 2017, I continue as a PhD student at the same Institution in the newly formed Division of Tumor
Biology and immunology in the group of Heinz Jacobs. Here, I will examine the sensitivity of cancer cells lacking specific (DNA) translesion synthesis (TLS) polymerases for alkylating agents. TLS polymerases can continue replication opposite a modified DNA templates. We hope that our insights improve chemotherapy and  provide novel strategies for precision cancer medicine.

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Research updates View All Updates

  • Heinz Jacobs recently received a grant from the Dutch Cancer Foundation (KWF): NKI 2012-5713, to explore the role of DNA-Damage Tolerance as a Drug-Target for Chemosensitization and a Mechanism of Chemoresistance

Key publications View All Publications

  • Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production

    PNAS 2011; 108:10644-9

    Lutz J*, Heideman M*, Roth E, van den Berk P, Müller W, Raman C, Wabl M, Jacobs H*, and Jäck H-M*. (* shared contribution).

    Link to PubMed
  • Dependence of nucleotide substitutions on Ung2, Msh2, and PCNA-Ub during somatic hypermutation

    J Exp Med. 2009; 206: 2603-11

    Krijger PH, Langerak P, van den Berk PC, Jacobs H.

    Link to PubMed
 
 

Recent publications View All Publications

  • Roles of PCNA ubiquitination and TLS polymerases κ and η in the bypass of methyl methanesulfonate-induced DNA damage

    Nucleic Acids Res. 2015 Jan;43(1):282-94

    Wit N, Buoninfante OA, van den Berk PC, Jansen JG, Hogenbirk MA, de Wind N, Jacobs H

    link to PubMed
  • Rev1 is essential in generating G to C transversions downstream of the Ung2 pathway but not in the Msh2/Ung2 hybrid pathway

    Eur. J. Immunol. 2013; in press.

    Krijger PHL, Tsaalbi-Shtylik A, Jansen JG, van den Berk PCM, Wit N, de Wind N, and Jacobs H.

    Read more
 

Contact

  • Office manager

    Karin van der Heijden

  • E-mail

    k.vd.heijden@nki.nl

  • Telephone Number

    +31 20 512 2055

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