Cohesinopathies are genetic instability syndromes associated with defects in the regulators and structural components of the cohesin complex (figure 1). This complex is involved in sister chromatid cohesion, a process that keeps the newly replicated chromosomes together from the time of their synthesis in S phase until they separate during mitosis.
A cohesinopathy that we are focussing on is Roberts syndrome (RBS) . In this disease the cohesion between the sister chromatids generated after DNA replication is disturbed due to a mutation in the putative acetyltransferase ESCO2, as discovered by our group in 2005.
We have generated functionally corrected immortal skin fibroblasts from a RBS patient and showed that ESCO2 is not only involved in sister chromatid cohesion, but also in protection against DNA damaging agents that interfere with DNA replication. This leads to crosslinker sensitivity and may result in aneuploidy.
We also identified a novel cohesinopathy due to mutations in the helicase DDX11, which we designated Warsaw Breakage Syndrome (WABS) after the origin of the first affected individual. Also in this case we functionally corrected cell lines from the WABS patient for further characterization of the DDX11 protein. The WABS patient nicely connects our FA and RBS work, since the patient shows the cellular characteristics of both syndromes. In addition, DDX11 and FANCJ belong to the same family of iron-sulfur containing helicases.
We are investigating the role of DDX11 and ESCO2 in sister chromatid cohesion and try to relate this function and that of other proteins involved in sister chromatid cohesion to aneuploidy and cancer.
Figure 1. Cohesinopathies are associated with defects in sister chromatid cohesion. The cohesion complex, consisting of Smc1, Smc3, Scc1 and Scc3 is loaded onto chromatin by Scc2/Scc4. During replication Smc3 is acetylated by Eco1, which counteracts the anti-establishment function of Pds5/Wpl through binding of sororin. In metaphase cohesion is removed by cleavage of Scc1. ESCO2 is one of the two human orthologs of Eco in yeast.
Wu Y, Sommers J, Khan I, de Winter JP and Brosh R. Biochemical characterization of Warsaw Breakage Syndrome helicase. J Biol Chem. 287: 1007-1021, 2012
Van der Lelij P, Chrzanowska KH+, Godthelp BC, Rooimans MA, Oostra AB, Stumm M, Zdzienicka MZ, Joenje H and de Winter JP+. Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1. Am J Hum Genet 86: 262-266, 2010
Van der Lelij P, Godthelp BC, van Zon W, van Gosliga D, Oostra AB, Steltenpool J, de Groot J, Scheper RJ, Wolthuis RM, Waisfisz Q, Darroudi F, Joenje H and de Winter JP. The cellular phenotype of Roberts syndrome fibroblasts as revealed by ectopic expression of ESCO2. PLoS ONE 4: e6936, 2009
Vega H, Waisfisz Q, Gordillo M, Sakai N, Yanzgihara I, Yamada M, van Gosliga D, Kayserili H, Xu, C, Ozono K, Jabs EW, Inui K and Joenje H. Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nat Genet 37: 468-470, 2005