This website uses cookies

This websites contains videos from YouTube. This company uses cookies (third party cookies). If you do not want them to use these cookies, you can indicate so here. However, this does mean that you will not be able to watch videos on this website. We also make use of our own cookies in order to improve our website. We don’t share our data with other parties. Read more about our cookie policy

This website uses cookies to enable video and to improve the user experience. If you do not want to accept these cookies, indicate so here. Read more about our cookie policy

Ga direct naar de inhoud, het hoofdmenu, het servicemenu of het zoekveld.

Biological Stress Response: Heinz Jacobs

Heinz Jacobs.jpg

Heinz Jacobs, Ph.D.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

silhouette_geen_foto_thumb_man.jpg

Marc Hogenbirk

PhD student

Experience

Close this window
silhouette_geen_foto_thumb_man.jpg

Paul van den Berk, MSc

Research technician

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.

Close this window
silhouette_geen_foto_thumb_vrouw.jpg

Olimpia Allessandra Buoninfante

PhD student

Experience

I am graduated in Pharmaceutical Biotechnology and conducted my training at "Sapienza" University of Roma and at University of Groningen, studying molecular mechanisms and main factors involved in development of neurodegenerative diseases such as Alzheimer's disease. My PhD project is focused on exploring DNA damage tolerance (DDT) in as a drug target for chemosensitization and a mechanism of chemoresistance. Since effective DDT depends on site-specific PCNA-ubiquitination, I will prohibit this site-specific ubiquitination process at genetic and biochemical levels in cell lines and in mouse tumors models. The aim of my work is to reveal the relevance of DDT as a drug target for cancer treatment and cancer progression.

Close this window
silhouette_geen_foto_thumb_man.jpg

Muhammad Assad Aslam, MSc

PhD student

Experience

Close this window
silhouette_geen_foto_thumb_man.jpg

Farshid Alemdehy

Postdoctoral fellow

Experience

I completed my PhD in the lab of Stefan Erkeland at the Erasmus MC Cancer Institute, Rotterdam, where I studied the role of microRNAs during normal and malignant myelopoiesis. As a Postdoctoral fellow in Heinz Jacobs lab, I am interested in developmental changes associated with the Ig heavy chain checkpoint in early B cell development.

 

Close this window
Pilzecke, Bas

Bas Pilzecker

PhD student

Experience

Currently, I work on the translesion synthesis and more specifically PCNA K164R involvement in translesion synthesis and interaction with translesion synthesis polymerases. The K164R mutation leaves cells highly
sensitive to alkylating agents, therefore we are also exploring PCNA K164 ubiquitination inhibition as chemosensitization strategy. During my master Cancer Genomics and Developmental Biology in Utrecht, I did internships in the Korswagen lab at the Hubrecht Institute on C. elegans and Wnt signaling

I did my second intern in the Innocenti lab at the NKI/AVL, where I studied mDia2 in  filopodia formation.

Close this window

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

    Thea Eggenhuizen

  • E-mail

    t.eggenhuizen@nki.nl

  • Telephone Number

    +31 20 512 2035

Eggenhuizen, Thea.jpg

Donate

'Research for the benefit of cancer patients'

Support us
Share this page