The cohesin complex is involved in multiple aspects of genome organization. These include gene transcription, DNA repair and sister chromatid cohesion; the tethering of sister chromatids to enable their proper distribution in mitosis. Several rare developmental disorders, termed ‘cohesinopathies’ are characterized by impaired cohesin functioning. In addition, cohesin components are frequently mutated in cancer and loss of sister chromatid cohesion can be detected in many cancer cell lines, upon activation of oncogenes in normal cells and by genetic or pharmacological perturbation of DNA replication.

 The cohesion team studies fundamental cohesion biology and investigates how deregulation of cohesin functions affect cell fate and disease etiology. We address these questions by using a wide range of genetic, biochemistry, microscopy and cell biology approaches. This will increase our understanding of the diverse activities of cohesion and may provide clinical opportunities if specific vulnerabilities of cancer cells with defective cohesion can be identified and targeted.

Selected Publications

Van Schie JJM, de Lint K, Molenaar TM, Moronta Gines M, Balk JA, Rooimans MA, Roohollahi K, Pai GM, Borghuis L, Ramadhin AR, Corazza F, Dorsman JC, Wendt KS, Wolthuis RMF, De Lange J (2023). CRISPR screens in sister chromatid cohesion defective cells reveal PAXIP1-PAGR1 as regulator of chromatin association of cohesin. Nucleic Acids Res. 2023 Sep 13:gkad756.

Van Schie JJM, de Lint K, Pai GM, Rooimans MA, Wolthuis RMF, De Lange J (2022). MMS22L-TONSL functions in sister chromatid cohesion in a pathway parallel to DSCC1-RFC. Life Sci Alliance; 6(2): e202201596

Carvalhal S, Bader I, Rooimans M.A., Oostra A.B., Balk J.A., Feichtinger R.G., Beichler C., Speicher M.R., van Hagen J.M., Waisfisz Q., van Haelst M., Bruijn M., Tavares A., Mayr J.A., Wolthuis R.M.F., Oliveira R.A., De Lange J (2022). Biallelic BUB1 mutations cause microcephaly, developmental delay and variable effects on cohesion and chromosome segregation. Science Advances ;8(3):eabk0114

Van Schie, J.J.M. and De Lange J (2021). The Interplay of Cohesin and the Replisome at Processive and Stressed DNA Replication Forks. Cells 10(12)

Van Schie, J.J., Faramarz, A., Balk, J.A., Stewart, G.S., Cantelli, E., Oostra, A.B., Rooimans, M.A., Parish, J.L., de Almeida Estéves, C., Dumic, K., Barisic, I., Diderich, K.E.M., van Slegtenhorst, M.A., Mahtab, M., Pisani, F.M., te Riele, H., Ameziane, N., Wolthuis, R.M.F., De Lange, J. (2020). Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion. Nat. Comm. 11:1-18

Benedict, B., van Schie, J.J.M., Oostra, A.B., Balk, J.A., Wolthuis, R.M.F., te Riele, H., De Lange, J. (2020) WAPL-dependent repair of damaged DNA replication forks underlies oncogene-induced loss of sister chromatid cohesion. Dev. Cell 52:683-698.

De Lange, J., Faramarz, A., Oostra, A.B., De Menezes, R.X., van der Meulen, I.H., Rooimans, M.A., Rockx, D.A., Brakenhoff, R.H., van Beusechem, V.W., King, R.W., Wolthuis, R.M.F. (2015). Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function. Nat. Comm. 6:1-12