Research interest
Genetic instability and deregulated cell cycle control are hallmarks of human cancer. Our research involves both aspects focusing on (i) the role of DNA mismatch repair and the Fanconi anemia pathway in mutation avoidance, and (ii) the role of cell cycle checkpoints in tumor suppression.
DNA Mismatch Repair
Genetic defects in DNA mismatch repair (MMR) underlie the cancer syndrome hereditary non-polyposis colorectal cancer (HNPCC). The primary function of MMR is correction of DNA replication errors. In addition, MMR suppresses DNA damage-induced mutagenesis and counteracts homologous recombination between slightly diverged DNA sequences. By generating mouse embryonic stem cells (ES cells) with targeted disruptions in MMR genes and mouse lines derived thereof, we investigate which of these functions is critical to suppression of tumorigenesis.
In particular, we are generating, by oligonucleotide-directed gene modification, specific codon substitutions in the central MMR gene Msh2 to uncouple MMR functions and to study the role of each in tumor suppression.
Oligonucleotide-directed gene modification
We have recently found that sequence-specific single-stranded oligonucleotides of ±38 deoxyribonucleotides can be used to insert or substitute one or a few base pairs at any desired location in the ES cell genome and have shown that mutant alleles can be introduced into the mouse germ line. However, oligo targeting is severely hampered by DNA mismatch repair activity (Dekker et al., NAR 2003;31:e27). We therefore make cells permissive for oligonucleotide-directed gene modification by transiently disabling the MMR machinery. We are exploiting this procedure to study the pathogenicity of allelic variants found in the human population, focusing on RB, p53 and MSH2/6.
Fanconi anemia
Fanconi anemia is a recessive hereditary disease leading to developmental malformations, progressive anemia and predisposition to cancer. Thus far, 13 genes have been implicated in Fanconi anemia. At the cellular level, loss of any of these genes leads to cell killing and chromosomal aberrations by DNA crosslinking agents. In collaboration with the group of Hans Joenje and Johan de Winter at the Free University Medical Center Amsterdam, we are studying the consequences of genetic defects in the Fanconi anemia pathway for the etiology and behavior of tumors.
Cell cycle checkpoints
Loss of G1-S control is a hallmark of cancer. However, we found that loss of the G1-S checkpoint in mouse embryonic fibroblasts (MEFs) with defects in the retinoblastoma gene family (TKO MEFs, lacking expression of Rb, p107 and p130) is not sufficient for unrestricted proliferation. E.g., we found that mitogen-deprived TKO MEFs can enter and complete S-phase but then undergo apoptosis or arrest in the G2 phase of the cell cycle. We are currently investigating the mechanism of G2 arrest, its involvement in restricting proliferation under a number of growth-inhibiting conditions and its significance as a suppressor mechanism of oncogenic transformation in vivo.
Key publications
Aarts M, Dekker M, De Vries S, Van der Wal A, Te Riele H (2006) Generation of a mouse mutant by oligonucleotide-mediated gene modification in ES cells. Nucleic Acids Res 34, e147.
Foijer F and Te Riele H (2006) Check, double check: The G2 barrier to cancer. Cell Cycle 5, 831-836.
Dannenberg, J.-H. and Te Riele, H.J.P. (2006) The Retinoblastoma Gene Family in Cell Cycle Regulation and Suppression of Tumorigenesis. In: Kaldis, P. (ed.) Cell Cycle Regulation. Results and Problems in Cell Differentiation, vol. 42. Springer Berlin, Heidelberg, New York, pp 183-226.
Dekker M, Brouwers C, Aarts M, Van der Torre J, De Vries S, Van de Vrugt H, Te Riele H (2006) Effective oligonucleotide-mediated gene disruption in ES cells lacking the mismatch repair protein MSH3. Gene Ther 13, 686-694.
Foijer F, Wolthuis RMF, Doodeman D, Medema RM, Te Riele H (2005) Mitogen requirement for cell cycle progression in the absence of pocket protein activity. Cancer Cell 8, 455-66.
Dannenberg, J-H, Schuijff L, Dekker M, Van der Valk M and Te Riele H (2004) Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Genes Dev 18, 2952-2962.
Dekker M, Brouwers C, Te Riele H (2003) Targeted gene modification in mismatch-repair-deficient embryonic stem cells by single-stranded DNA oliogonucleotides. Nucleic Acids Res 31, e27.
Claij N, and Te Riele, H (2002) Methylation tolerance in mismatch repair proficient cells with low MSH2 protein level. Oncogene 21, 2873-2879.
Dannenberg J-H, Van Rossum A, Schuijff L, and Te Riele H. (2000) Ablation of the retinoblastoma gene family deregulates G1 control causing immortalization and increased cell turnover under growth-restricting conditions. Genes Dev 14, 3051-3064.
De Wind, N., Dekker, M., Claij, N., Jansen, L., Van Klink, Y., Radman, M., Riggins, G., Van der Valk, M., Van 't Wout, K., and Te Riele, H. (1999) HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. Nat. Genet. 23, 359-362.
More publications by Hein te Riele on PubMed
Biographic sketch
Hein te Riele (1955) studied chemistry at the University of Groningen and obtained his PhD in 1984 with the thesis: “Heterospecific transformation in Bacillus subtilis” (promotor: prof. dr Gerard Venema). He then spent 4 years as a postdoctoral fellow at the Institut Jacques Monod in Paris with Dusko Ehrlich and found a novel mechanism of plasmid replication. In 1988, he became a cancer researcher supported by grants from the Dutch Cancer Society. He joined the group of Anton Berns at the Netherlands Cancer Institute, where he helped optimizing procedures for targeted gene modification in mouse embryonic stem cells and generated a mouse model for retinoblastoma. In 1994 he started his own research group and in 2000 he became head of the division of Molecular Biology. Hein te Riele is professor at the Free University Amsterdam (chair: Genetic instability and carcinogenesis), president of the Netherlands Genetics Society and member of the Health Council of the Netherlands.
Co-workers
Rob Dekker PhD Post-doc
Camiel Wielders PhD Post-doc
Marieke Aarts MSc Graduate student
Sietske Bakker MSc Graduate student
Tanja van Harn MSc Graduate student
Tinke Vormer MSc Graduate student
Eva Wielders Msc Graduate student
Marleen Dekker Technical staff
Elly Delzenne-Goette Technical staff
Sandra De Vries MSc Technical staff
Anja Van der Wal Technical staff
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