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.
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., 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. doi.org/10.1016/j.devcel.2020.01.024
Faramarz, A., Balk, J.A., van Schie, J.J.M., Oostra, A.B, Ghandour, C.A., Rooimans, M.A., Wolthuis, R.M.F., de Lange, J. (2020) Non-redundant roles in sister chromatid cohesion of the DNA helicase DDX11 and the SMC3 acetyl transferases ESCO1 and ESCO2. PLoS One 15: e0220348.
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