Research interest
The focus of this group is programmed mutagenesis, DNA damage tolerance and their contribution to genetic instability and cancer development. In this context, we are particularly interested in the aberrant targeting of programmed mutagenesis, the identity of damage tolerant polymerases involved in the mutagenic processing of DNA lesions, and the decision making between mutagenic and non-mutagenic pathways of DNA damage tolerance. Our approaches involve basic and advanced molecular genetics, biochemistry, immunology and recombinant mouse genetics.
Cause and consequences of aberrant targeting of programmed mutagenesis B cells use programmed mutagenesis to diversify immunoglobulin genes. The activation induced cytidine deaminase (AID) triggers this highly mutagenic process by deaminating cytosine residues in the variable and switch regions of immunoglobulin genes. Aberrant targeting of AID has been implicated in the accumulation of oncogenic mutations. To establish molecular signatures contributing to AID targeting and identify genome wide aberrant AID Target Sites (ATS) we established the DamID technology for non-adherent cells. These ATS will help us to map cancer-associated AID Target Sites (CATS) that determine the clinical outcome, tumor behavior, prognosis and treatment of B cell non-Hodgkin lymphoma.
Mutagenic processing To establish somatic mutations from the 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 lesions, albeit often at the expense of accuracy. We are studying recombinant mouse models and combinations thereof to determine the contribution of individual TLS polymerases and their functional domains to the mutation process.
Decision making Studies in yeast indicate that error prone translesion synthesis (TLS) depends on mono-ubiquitination at lysine164 of proliferating cell nuclear antigen (PCNAK164). Knock-in mice homozygous for a PCNAK164R mutation indicate that this pathway of damage tolerance is conserved from yeast to mammals. Moreover, B cells use PCNAUb dependent TLS to generate somatic mutations. Currently we are testing whether mismatch recognition, PCNAUb and Polh are epistatic in establishing mutations at template A/T during replication of Ig genes.
Biographic sketch
Heinz Jacobs received his PhD from the University of Amsterdam where he studied 'T Cell Development in TCR Mutant Mice' in the laboratory of Anton Berns. In 1994 he was awarded an EMBO longterm post-doc fellowship to work on 'The Molecular Mechanism Underlying Somatic Hypermutation' and joined the group of Klaus Rajewsky at the Institute for Genetics in Cologne, Germany. Here, he characterized the role of transcription in somatic hypermutation of immunoglobulin genes and its relation to DNA repair pathways. In 1996 the applicant was offered an independent group leader position at the Basel Institute for Immunology, Basel, Switzerland. During this period the applicants group discovered that DNA strand breaks are frequent in variable region of immunoglobulin genes undergoing somatic hypermutation. In addition, two independent approaches were established to identify genes controlling malignant and normal lymphocyte development. In 2002 he was appointed senior staff scientist at the Netherlands Cancer Institute where he studies 'Programmed mutagenesis, DNA damage tolerance and their causal relation to cancer development'. In 2004 the applicant was awarded a VIDI program 'Role of Translesion DNA synthesis in Immunity and Cancer Development' from The Netherlands Organization for Health Research and Development.
Key publications
Langerak P., Nygren A.O.H., Krijger P.H.L., van den Berk, P.C.M., and Jacobs H. (2007). A/T mutagenesis in hypermutated Ig genes strongly depends on PCNA K164 modification. J. Exp. Med.; 204:1989-98.
Langerak P.*, Jansen J.G.*, Tsaalbi-Shtylik A., van den Berk P., de Wind N.*, and Jacobs H.* (2006). Strand-biased defect in C/G transversions in hypermutating Immunoglobulin genes in Rev1-deficient mice. J. Exp. Med.; 203:319-323. (* = equal contribution.)
Schnell S., Démollière C., van den Berk P., and Jacobs, H. (2006). Gimap4 accelerates T-cell death. Blood. 108:591-9.
Langerak P, Nygren AO, Schouten JP, and Jacobs H. (2005). Rapid and quantitative detection of homologous and non-homologous recombination events using three oligonucleotide MLPA. Nucleic Acids Res. 33(22):e188.
Bross L., Muramatsu M., Kinoshita, K., Honjo T., and Jacobs, H. (2002). DNA Double -Strand Breaks: Prior to but not sufficient in targeting hypermutation. J. Exp. Med. 195:1187-1192.
Jacobs H. and Bross L. (2001). Towards an Understanding of Somatic Hypermutation. Cur. Opin. in Immunol. 13:208-218.
Bross L., Fukita, Y., McBlane F., Démollière C., Rajewsky K., and Jacobs H. (2000). DNA Double-Strand Breaks in Immunoglobulin Genes Undergoing Somatic Hypermutation. Immunity, 13:589-597.
Jacobs H. (2000). TCR-Independent T Cell Development Mediated by Gain of Oncogene or Loss of Tumor Suppressor Gene Function. Sem. Immunol. 12:487-502.
Jacobs H., Krimpenfort P., Haks M., Allen J., Blom B., Démollière C., Kruisbeek A., Spits H., and Berns A. (1999). Pim1 reconstitutes thymus cellularity in IL-7 and gc-mutant mice and permits thymocyte maturation in Rag- but not CD3g deficient mice. J. Exp. Med. 190: 1059-1068.
Jacobs H., Puglisi A., Rajewsky K., and Fukita Y. (1999). Tuning Somatic Hypermutation by Transcription. Cur. Topics in Microbiol. and Immunol., 246: 149-159.
Fukita Y., Jacobs H., and Rajewsky K. (1998). Somatic Hypermutation in the Heavy Chain Locus Correlates with Transcription. Immunity, 9: 105-114.
Jacobs H., Fukita Y., van der Horst G.T.J., de Boer J., Weeda G., Essers J., de Wind N., Engelward B.P., Samson L., Verbeek S., Ménissier de Murcia J., de Murcia G., te Riele H., and Rajewsky, K. (1998). Hypermutation of Immunoglobulin Genes in Memory B cells of DNA repair-deficient Mice. J. Exp. Med., 187: 1735-1743.
Co-workers
Schnell, Silke Postdoctoral fellow
Langerak, Petra MSc Graduate student
Heideman, Marinus MSc Graduate student
Krijger, Peter MSc Graduate student
Van den Berk, Paul Research assistant
Pan, Xiaojuan Undergraduate student