D. C. (Dik) van Gent, PhD

Dik van Gent  studied biology in Utrecht and did his PhD research at the Netherlands Cancer Institute (Amsterdam) under the supervision of Prof. R.H.A. Plasterk. He investigated various aspect of the HIV DNA integration reaction. After receiving his PhD in 1993, he did three years of post doc research at the National Institutes of Health in Bethesda (USA) under the supervision of Dr. M. Gellert.

During most of this time he was supported by an EMBO long term fellowship. He unraveled the basic mechanism of RAG1/2 mediated V(D)J recombination, which generates the antigen receptor diversity in B and T cells. For this work he received the biennial prize of the Netherlands Society of Biochemistry and Molecular Biology (NVBMB) in 1997. In 1996 he moved to the Erasmus University Rotterdam (now Erasmus MC), Department of Molecular Genetics. He received a KNAW fellowship to establish his own line of research here. Since then he received research funding from the Netherlands Scientific Organization (NWO), the Netherlands Cancer Foundation (KWF), the Association for International Cancer Research (AICR) and the European Union.

He studied many aspects of DNA double strand break repair, with emphasis on the non-homologous end-joining pathway. He authored approximately 70 peer-reviewed papers.

He is currently a board member of the Netherlands Society for Radiobiology (NVRB) and director of the Research Master program Molecular Medicine.

Research

The group studies various aspects of DNA double strand break repair, with an emphasis on a better understanding of DNA damaging anti-tumor therapies and how these therapies can be optimized for specific tumors. For this purpose we have developed novel technology to allow direct investigation of DNA damage responses in tumor tissue slices derived from fresh clinical samples. We also carry out more mechanistic studies, which currently concentrate mainly on DNA repair after radionuclide therapy and PARP inhibitor resistance mechanisms in BRCA-mutated tumors. 

DNA damage responses in tissues and tumors

In collaboration with the Departments of Urology and Pathology, we developed similar DNA damage response assays for bladder and prostate cancer. Again, the primary goal is to predict therapy response. We showed that expression levels of the Nucleotide Excision Repair (NER) protein XPC cannot be used to predict NER capacity of bladder tumors.

In collaboration with Prof. Casper van Eijck we are currently also adapting this technology to study gastrointestinal tumors, including neuroendocrine pancreas tumors.

Publications

• Naipal, K.A.T.,  Verkaik, N.S., Ameziane, N., van Deurzen, C.H.M., ter Brugge, P., Meijers, M., Sieuwerts, A.M., Martens, J.W., O’Connor, M.J., Vrieling, H., Hoeijmakers, J.H.J., Jonkers, J., Kanaar, R., de Winter, J.P., Vreeswijk, M.P., Jager, A., van Gent, D.C. (2014) Functional ex vivo assay to select Homologous Recombination deficient breast tumors for PARP inhibitor treatment. Clin. Cancer Res. 20,4816-26.
• Naipal, K.A.T., Raams, A., Bruens, S.T., Brandsma, I., Verkaik, N.S., Jaspers, N.G.J., Hoeijmakers, J.H.J., van Leenders, G.J., Pothof, J., Kanaar, R., Boormans, J. and van Gent, D.C. (2015) Attenuated XPC Expression Is Not Associated with Impaired DNA Repair in Bladder Cancer. PLoS One 10, e0126029. 
  
   

Mechanisms of DNA double strand break repair and PARP inhibitor resistance

We study various aspects of DNA double strand break repair, with an emphasis on the Non-homologous end-joining (NEHJ) pathway and on BRCA1/2 deficiency and PARP inhibitor sensitivity. We previously identified several NHEJ defects in Severe Combined Immuno Deficiency (SCID) patients and determined the functional consequences of these mutations. We also studied the basic mechanistic aspects of this DNA repair pathway using biochemistry, cell biology and animal models. Current research is concentrating on DNA repair defects in BRCA mutated tumors and how sensitivity and resistance to PARP inhibition are regulated.

Publications

• Mari, P.O., Florea, B.I., Persengiev, S.P., Verkaik, N.S., Brüggenwirth, H.T., Modesti, M.M., Giglia-Mari, G., Bezstarosti, K., Demmers, J.A.A., Luider, T.M., Houtsmuller, A.B. and van Gent, D.C. (2006) Dynamic Assembly of End-joining Complexes Requires Interaction between Ku70/80 and XRCC4. Proc. Natl. Acad. Sci. USA, 103, 18597-18602.
• Van der Burg, M., IJspeert, H., Verkaik, N.S., Turul, T., Wiegant, W.W., Morotomi-Yano, K., Mari, P.O., Tezcan, I., Chen, D.J., Zdzienicka, M.Z., van Dongen, J.J.M. and van Gent, D.C. (2009) DNA-PKcs Mutation In a T-B-SCID Patient Inhibits Artemis Activation and Non-Homologous End-Joining. J. Clin. Invest., 119, 91-98.
• Weterings, E., Verkaik, N.S., Keijzers, G., Florea, B.I., Wang, S.Y., Ortega, L.G., Uematsu, N., Chen, D.J. and van Gent, D.C. (2009) The Ku80 carboxy-terminus stimulates Joining and Artemis-mediated processing of DNA ends. Mol. Cell. Biol., 29, 1134-1142.
• Brugmans, L., Verkaik, N.S., Kunen, M., van Drunen, E., Williams, B.R., Petrini, J.H., Kanaar, R., Essers, J. and van Gent, D.C. (2009) NBS1 cooperates with homologous recombination to counteract chromosome breakage during replication. DNA Repair, 8, 1363-1370.
• Xu, G, Chapman, J.R., Brandsma, I., Yuan, J., Mistrik, M., Watanabe, K., Bouwman, P., Bartkova, L., Gogola, E., Warmerdam, D., Barazas, M., Jaspers, J.E., Pieterse, M., Kersbergen, A., Sol, W., Celie, P., van den Broek, B., Salman, A., Nieuwland, M., de Rink, I., de Ronde, J., Jalink, K., Boulton, S.J., Chen, J., van Gent, D.C., Bartek, J., Jonkers, J., Borst, P. and Rottenberg, S. (2015) REV7 counteracts DNA double-strand break resection and its loss causes PARP inhibitor resistance of BRCA1-deficient mammary tumors. Nature 521, 541-4
• De Bruin, C., Mericq, V., Andrew, S.F., van Duyvenvoorde, H.A., Verkaik, N.S., Losekoot, M., Porollo, A., Garcia, H., Kuang, Y., Hanson, D., Clayton, P., van Gent, D.C., Wit, J.M., Hwa, V., Dauber, A. (2015). An XRCC4 Splice Mutation Associated With Severe Short Stature, Gonadal Failure, and Early-Onset Metabolic Syndrome. J. Clin. Endocrinol. Metab. 100, E789-98. 

Key publications

• Van der Burg M, IJspeert H, Verkaik NS, Turul T, Wiegant WW, Morotomi-Yano K, Mari PO, Tezcan I, Chen DJ, Zdzienicka MZ, van Dongen JJM, and van Gent DC (2009). DNA-PKcs Mutation In a T-B-SCID Patient Inhibits Artemis Activation and Non-Homologous End-Joining J Clin Invest 119:91-98.
• Weterings E, Verkaik NS, Keijzers G, Florea BI, Wang SY, Ortega LG, Uematsu N, Chen DJ and van Gent DC (2009). The Ku80 carboxy-terminus stimulates Joining and Artemis-mediated processing of DNA ends. Mol Cell Biol 29:1134-1142.
• Pothof J, Verkaik NS, van IJcken W, Wiemer EAC, Ta VTB, van der Horst GTJ, Jaspers NGJ, van Gent DC, Hoeijmakers JHJ, and Persengiev SP (2009). MicroRNA-mediated Gene Silencing Modulates the UV-induced DNA Damage Response. EMBO J 28:2090-2099. 
• Pothof J, Verkaik NS, Hoeijmakers JHJ, and van Gent DC (2009). MicroRNA responses and stress granule formation modulate the DNA damage response. Cell Cycle 8:3462-3468. 
• Van Gent DC and van der Burg M (2007). Non-Homologous End-Joining, a Sticky Affair. Oncogene, 26, 7731-7740. 
• Mari PO, Florea BI, Persengiev SP, Verkaik NS, Brüggenwirth HT, Modesti MM, Giglia-Mari G, Bezstarosti K, Demmers JAA, Luider TM, Houtsmuller AB and van Gent DC (2006). Dynamic Assembly of End-joining Complexes Requires Interaction between Ku70/80 and XRCC4. PNAS USA, 103, 18597-18602.
• Van Gent DC, Hoeijmakers JHJ, and Kanaar R (2001). Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2:196-206.

Teaching

Dik van Gent is involved in teaching at various levels. He is coordinator of the Oncology course for second year medical students. He also coordinates the minor ‘Biomedical research in practice’ for third year medical students and Erasmus University College students. Furthermore, he is director of the MSc programme Molecular Medicine, which offers a two year master of science curriculum for medical and biomedical students, where student study molecular cell biology in the context of medically relevant research topics.

Contact information:
Dr. Dik C. van Gent
Dept. of Molecular Genetics
Erasmus MC
PO Box 2040
3000 CA Rotterdam
The Netherlands
Tel. +31-10-7043932
e-mail: d.vangent@erasmusmc.nl 

Ba ‘Oncology’
In the second year of their curriculum, medical students follow a 13-week course on basic, clinical and psychological aspects of cancer. Students learn step by step how a normal cell becomes a cancer cell and a tumor. Subsequently, they learn how the general and tumor type specific treatment is currently organized. Finally, students also get a perspective of the fast moving field of modern fundamental and clinical cancer research. Dr. Dik van Gent coordinates this course, together with a medical oncologist, Dr. Ferry Eskens. He also coordinates two of the three integrated exams. 

Minor ‘Biomedical Research in Practice’
At the start of their third year, medical students and Erasmus University College students can choose to follow an in depth course on biomedical research. They get a firm basis in molecular cell biology and learn how to work in a modern biomedical research setting. Dr. Dik van Gent coordinates this 10-week course teaches several elements in this course and coordinates the examination.

MSc Molecular Medicine