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Bekaert, S.-L.

Publications and source records attributed to Bekaert, S.-L..

2 recordsLinked to original sources

Preclinical exploration of the DNA Damage Response pathway using the interactive neuroblastoma cell line explorer CLEAN.

Neuroblastoma (NB) is the most common cancer in infancy with an urgent need for more efficient targeted therapies. The development of novel (combinatorial) treatment strategies relies on extensive explorations of signaling perturbations in neuroblastoma cell lines, using RNA-Seq or other high throughput technologies (e.g., phosphoproteomics). This typically requires dedicated bioinformatics support, which is not always available. Additionally, while data from published studies are highly valuable and raw data (e.g., fastq files) are nowadays released in public repositories, data processing is time-consuming and again difficult without bioinformatics support. To facilitate NB research, more user-friendly and immediately accessible platforms are needed to explore newly generated as well as existing high throughput data. To make this possible, we developed an interactive data centralization and visualization web application, called CLEAN (the Cell Line Explorer web Application of Neuroblastoma data; https://ccgg.ugent.be/shiny/clean/). By focusing on the regulation of the DNA damage response, a therapeutic target of major interest in neuroblastoma, we demonstrate how CLEAN can be used to gain novel mechanistic insights and identify putative drug targets in neuroblastoma.

cancer biology↗

The chromatin reader PHF6 at the crossroad of the replication stress and DNA damage responses in neuroblastoma through interaction with RRM2

The PHF6 protein is a presumed chromatin reader implicated in disease through germline loss-of-function mutations causing cognitive disability syndromes and somatic mutations are predominantly observed in acute T-cell leukemia. Previous reports support a role for PHF6 in DNA damage repair, replication fork restart as well as hematopoietic precursor cell self-renewal capacity and lineage commitment. To explore better how PHF6 mediates these functions, we mapped the PHF6 interactome and identified RRM2 as a consistent binding partner across different normal and malignant cell types. Next, PHF6 knockdown imposed increased replicative stress/DNA damage and suggested possible binding of PHF6 to H3K56ac, a marker for nascent DNA at sites of DNA damage repair. Genome-wide mapping of PHF6 chromatin binding indeed revealed overlap with sites of active DNA damage, binding sites of replication fork proteins and functional crosstalk with the neuroblastoma transcription core regulatory circuitry. Altogether, we show a canonical PHF6-RRM2 interaction enabling active transport of RRM2 to genomic sites of PHF6 mediated fork restart and PHF6 localization to H3K56ac at highly transcribed genes facilitating fork restart following replication-transcription conflicts.

cancer biology↗