Job de Lange

PhD, MSC.

20102020

Research output per year

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Personal profile

Specialisation

My research line focuses on 'sister chromatid cohesion'; the process that duplicated chromosomes (the sister chromatids) remain connected from the time of their synthesis in S-phase until their separation in anaphase, to allow the proper distribution of DNA over two new daughter cells. We found that cohesion is critically impaired in cancer cells and that this could serve as a unique and targetable vulnerability. To further pursue this reasearch line, I received a position as a junior group leader and KWF awarded me with a Young Investigator Grant in 2017.

Current focus lies particularly in understanding the cohesion loss that occurs upon oncogene-induced DNA replication stress, as well as functional studies of the DNA helicase DDX11, which is mutated in the cohesinopathy Warsaw Breakage Syndrome

Research interests

I am interested in how cells organize and transfer their DNA, how deregulation of these complex mechanisms affect cell fate and diseases such as cancer, and how we may be able to exploit the understanding to identify footholds for therapeutic benefit.

Every time a human cell divides, 46 chromosomes need to be duplicated and divided over two daughter cells. In order to provide each daughter cell with the exact right set of 46 chromosomes, the sister chromatids are stably entrapped by large, circular protein complex named cohesins. The resulting sister chromatid cohesion allows sister chromatids to be orderly aligned in metaphase and attached to microtubules from opposite poles. Upon cohesin cleavage, they can be properly separated and distributed over two new cells.

We study conditions that challenge normal cohesion. Several rare developmental disorders are characterized by premature cohesion loss. In addition, cohesion loss can be detected in many cancer cell lines, upon activation of oncogenes in normal cells and by genetic or pharmacological perturbation of DNA replication. In our lab, we try to answer questions such as: how does oncogenic transformation affect sister chromatid cohesion? How are cohesin dynamics regulated in the context of a normally progressing DNA replication fork, and in conditions of DNA replication stress? To what extent do cohesin mutations in cancer affect cohesin functions, and how does this contribute to tumorigenesis? Can we identify novel drug targets or synergistic drug combinations for tumor cells in which cohesion regulation is impaired? How does the DNA helicase DDX11 (mutated in the cohesinopathy Warsaw Breakage Syndrome) contribute to replication fork progression, sister chromatid cohesion and DNA damage response? We address these questions by using a wide range of genetic, biochemistry and microscopy approaches. This will increase our understanding of the complex interplay between sister chromatid cohesion and DNA replication, and may provide clinical opportunities if specific vulnerabilities of cancer cells with defective cohesion can be found and targeted.

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Research Output

WAPL-Dependent Repair of Damaged DNA Replication Forks Underlies Oncogene-Induced Loss of Sister Chromatid Cohesion

Benedict, B., van Schie, J. J. M., Oostra, A. B., Balk, J. A., Wolthuis, R. M. F., Riele, H. T. & de Lange, J., 23 Mar 2020, In : Developmental Cell. 52, 6, p. 683-698.e7

Research output: Contribution to journalArticleAcademicpeer-review

Open Access

Non-redundant roles in sister chromatid cohesion of the DNA helicase DDX11 and the SMC3 acetyl transferases ESCO1 and ESCO2

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, In : PLoS ONE. 15, 1, p. e0220348 e0220348.

Research output: Contribution to journalArticleAcademicpeer-review

Open Access

Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function

de Lange, J., Faramarz, A., Oostra, A. B., Menezes, R. X., van der Meulen, I. H., Rooimans, M. A., Rockx, D. A., Brakenhoff, R. H., van Beusechem, V. W., King, R. W., de Winter, J. P. & Wolthuis, R. M. F., 2015, In : Nature Communications. 6, 8399.

Research output: Contribution to journalArticleAcademicpeer-review

High levels of Hdmx promote cell growth in a subset of uveal melanomas

de Lange, J., Teunisse, A. F., Vries, M. V., Lodder, K., Lam, S., Luyten, G. P., Bernal, F., Jager, M. J. & Jochemsen, A. G., 2012, In : American Journal of Cancer Research. 2, 5, p. 492-507 16 p.

Research output: Contribution to journalArticleAcademicpeer-review

MDM4 is a key therapeutic target in cutaneous melanoma

Gembarska, A., Luciani, F., Fedele, C., Russell, E. A., Dewaele, M., Villar, S., Zwolinska, A., Haupt, S., de Lange, J., Yip, D., Goydos, J., Haigh, J. J., Haupt, Y., Larue, L., Jochemsen, A., Shi, H., Moriceau, G., Lo, R. S., Ghanem, G., Shackleton, M. & 2 others, Bernal, F. & Marine, J-C., 2012, In : Nature Medicine. 18, 8, p. 1239-1247

Research output: Contribution to journalArticleAcademicpeer-review