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.

Mechanisms of DNA double strand break repair and PARP inhibitor resistance


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.