Research interest
Genetic instability and deregulated cell cycle control are hallmarks of human cancer. Our research involves both aspects focusing on (i) cancer predisposition by defects in DNA mismatch repair and the Fanconi anemia pathway, 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/Lynch syndrome). MMR corrects DNA replication errors but also suppresses DNA damage-induced toxicity and mutagenesis and counteracts homologous recombination between slightly diverged DNA sequences. By disrupting or modifying MMR genes in mouse embryonic stem cells (ESC) and mice, we investigate which of these functions is critical to suppression of tumorigenesis.
Oligonucleotide-directed gene modification
We have recently developed a novel technique to insert or substitute one or a few base pairs at any desired location in the ESC genome, which makes use of sequence-specific single-stranded oligodeoxyribonucleotides (ssODN) of ±35 residues. However, “oligo targeting” is severely hampered by DNA mismatch repair activity and therefore we need to transiently disable the MMR machinery by RNA interference (Aarts et al., NAR 2006;34:e147). We are exploiting this procedure to recreate and study allelic variants of cancer-related genes found in the human population, focusing on RB, p53 and MSH2/6.
Fanconi anemia
Fanconi anemia (FA) is a recessive hereditary disease characterized by developmental malformations, progressive anemia and cancer predisposition. At the cellular level, loss of any of the 13 genes that have been implicated in FA 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 VU University Medical Center Amsterdam, we are studying the consequences of genetic defects in the FA pathway for the etiology and behavior of tumors.
Cell cycle checkpoints?
Loss of G1-S control is a hallmark of cancer. However, while full ablation of the retinoblastoma gene family (Rb, p107, p130) abrogates the G1-S checkpoint in mouse embryonic fibroblasts (MEFs), this is not sufficient for unrestricted proliferation. E.g., mitogen-deprived TKO MEFs can enter and complete S-phase but then undergo apoptosis or arrest in G2. This G2 arrest is accompanied by severe DNA damage and cohesion defects. 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 or promoter of oncogenic transformation in vivo.
Key publications
Wielders EAL, Dekker RJ, Holt I, Morris GE and Te Riele H (2011) Characterization of MSH2 variants by endogenous gene modification in mouse embryonic stem cells. Human Mutation in press.
Aarts M and Te Riele H (2010) Progress and prospects: oligonucleotide-directed gene modification in mouse embryonic stem cells: a route to therapeutic application. Gene Ther; December 16: doi:10.1038/gt.2010.161.
Van Harn T, Foijer F, van Vugt M, Banerjee R, Yang F, Oostra A, Joenje H, Te Riele H (2010) Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling. Genes Dev 24, 1377-138.
Aarts M, Te Riele H (2010b) Subtle gene modification in mouse ES cells: evidence for incorporation of unmodified oligonucleotides without induction of DNA damage. Nucleic Acids Res. [Epub ahead of print]
Bakker ST, van de Vrugt HJ, Rooimans MA, Oostra AB, Steltenpool J, Delzenne-Goette E, van der Wal A, van der Valk M, Joenje H, Te Riele H, de Winter JP (2009) Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M. Hum Mol Genet 18, 3484-95.
Vormer TL, Foijer F, Wielders CLC, Te Riele H (2008) Anchorage-independent growth of pocket-protein-deficient murine fibroblasts requires bypass of G2 arrest and can be accomplished by expression of TBX2. Mol Cell Biol 28, 7263-73.
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, 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.
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 (thesis: “Heterospecific transformation in Bacillus subtilis”; promotor: prof. dr Gerard Venema). He 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 VU University Amsterdam (chair: Genetic instability and carcinogenesis) and member of the Health Council of the Netherlands.
Co-workers
Rob Dekker PhD Postdoc
Camiel Wielders PhD Postdoc
Kamila Wojciechowicz-Grzadka Postdoc
Sietske Bakker MSc Graduate student
Tanja van Harn MSc Graduate student
Hellen Houlleberghs MSc Graduate student
Eva Wielders MSc Graduate student
Marleen Dekker Technical staff
Sandra de Vries Technical staff
Anja van der Wal Technical staff
Elly Delzenne-Goette Technical staff
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