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van den Broek, B.

Publications and source records attributed to van den Broek, B..

2 recordsLinked to original sources

DNA end-resection in highly accessible chromatin produces a toxic break

The authors have withdrawn their manuscript whilst they perform additional experiments to test some of their conclusions further. Despite repetitive attempts to reproduce the data shown in figure 2I, we have failed to obtain convincing evidence that chemical inhibition of Mre11 can improve the fitness of cells exposed to the so-called "halt" breaks. Upon re-analysis of the raw data used to compose figure 2I, we noted inconsistencies in the inclusion of datapoints, for which a satisfactory motivation was not apparent. In order to reproduce the experiments with the DNA-PK inhibitor, we ordered new batches of this compound, but noticed that the IC50 was significantly lower than that of the earlier batch (as determined in suppl. fig.1). While this might be due to a difference in batches, the IC50 of the newer batches was more comparable to the IC50 of this compound described for other cell lines. This sheds doubts on the quality of the batch used for the experiments shown in our manuscript, and we no longer wish to draw any conclusions based on these experiments. The authors hope that future experiments can resolve if open chromatin does indeed produce a potentially more toxic DNA break. The authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

cell biology

Sequence-dependent trafficking of GDE2, a GPI-specific phospholipase promoting neuronal differentiation

GDE2 is a six-transmembrane glycerophosphodiesterase with phospholipase D-like activity that cleaves select glycosylphosphatidylinositol (GPI)-anchored proteins and thereby influences biological signaling cascades. GDE2 promotes neuronal differentiation cell-autonomously through glypican cleavage and is a prognostic marker in neuroblastoma, while GDE2 deficiency causes progressive neurodegeneration in mice and developmental defects in zebrafish. However, the regulation of GDE2 remains unclear. Here we show that in undifferentiated neuronal cells, GDE2 undergoes constitutive internalization and traffics back along both fast and slow recycling routes, while a small percentage is sorted to late endosomes. GDE2 trafficking is dictated by distinctive C-terminal tail sequences that determine secretion, endocytosis and recycling preference, respectively, and thereby regulate GDE2 function both positively and negatively. Our study reveals the sequence determinants of GDE2 trafficking and surface localization, and provides insight into the control of GPI-anchored protein activities with potential implications for nervous system disorders associated with impaired trafficking and beyond.

neuroscience