A5061025641- Genomics and Chromatin Dynamics
- Innovative Microfluidic and Catalytic Techniques Innovation
- Microfluidic and Bio-sensing Technologies
- DNA Repair Mechanisms
- 3D Printing in Biomedical Research
- Epigenetics and DNA Methylation
- Chromatin Remodeling and Cancer
- CRISPR and Genetic Engineering
- Chromosomal and Genetic Variations
- Genomics and Phylogenetic Studies
- RNA Research and Splicing
- Sirtuins and Resveratrol in Medicine
- Genetics and Neurodevelopmental Disorders
- PARP inhibition in cancer therapy
- Histone Deacetylase Inhibitors Research
- Cancer Genomics and Diagnostics
- Cell Image Analysis Techniques
- Molecular Biology Techniques and Applications
- Nuclear Structure and Function
- Cellular transport and secretion
- Scientific Computing and Data Management
- Endoplasmic Reticulum Stress and Disease
- Protein Degradation and Inhibitors
- Advanced biosensing and bioanalysis techniques
- RNA modifications and cancer
Erasmus MC
2017-2024
Erasmus MC Cancer Institute
2021-2024
Oncode Institute
2024
Erasmus University Rotterdam
2020-2022
National Cancer Institute
2013-2021
National Institutes of Health
2014-2017
Significance In multicellular organisms, a single genome gives rise to multitude of cell types by enforcing appropriate gene expression patterns. Epigenetic mechanisms involving modification histones, including tri-methylation histone H3 lysine 9 (H3K9me3), assemble and propagate repressive heterochromatin prevent untimely expression. Dysregulation epigenetic gene-silencing is hallmark variety diseases cancer. However, the requirements for transmission are not well understood. This study...
Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability poorly understood. Here we discover a checkpoint-regulated cascade chromatin signalling that activates histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed forks. Using biochemical single molecule fibre approaches, show G9a together with SUV39h1 induces compaction by accumulating repressive...
Abstract The SWI/SNF family of ATP-dependent chromatin remodeling complexes is implicated in multiple DNA damage response mechanisms and frequently mutated cancer. BAF, PBAF ncBAF are three major types that functionally distinguished by their exclusive subunits. Accumulating evidence suggests double-strand breaks (DSBs) transcriptionally active preferentially repaired a dedicated homologous recombination pathway. We show different subunits promote rapidly recruited to DSBs...
Optimal treatment of cancer requires diagnostic methods to facilitate therapy choice and prevent ineffective treatments. Direct assessment response in viable tumor specimens could fill this gap. Therefore, we designed a microfluidic platform for patient using tissue slices under precisely controlled growth conditions. The optimized Cancer-on-Chip (CoC) maintained viability sustained proliferation breast prostate 7 days. No major changes morphology or gene expression patterns were observed...
Mild replication interference is a consolidated strategy for cancer chemotherapy. Tolerance to mild stress (RS) relies on active fork slowing, mediated by transient reversal and RECQ1-assisted restart, modulated PARP1 nuclear architectural components via yet-elusive mechanisms. We combined acute protein inactivation with cell biology single-molecule approaches investigate the role of Lamin A/C upon RS. found that dynamically interacts factories throughout nucleus and, together its...
The interplay of SMARCAD1-mediated active fork and BRCA1-mediated stalled stability pathways maintains genome integrity.
Hyperthermia inhibits DNA double-strand break (DSB) repair that utilizes homologous recombination (HR) pathway by a poorly defined mechanism(s); however, the mechanisms for this inhibition remain unclear. Here we report hyperthermia decreases H4K16 acetylation (H4K16ac), an epigenetic modification essential genome stability and transcription. Heat-induced reduction in H4K16ac was detected humans,
Significance Genome organization affects many critical nuclear functions. Notably, the periphery has emerged as a specialized compartment for regulation of transcription, replication, and DNA damage repair activities. Here, we find that cells carrying mutation in broadly distributed DNA-binding protein Sap1 experience replication stress genome instability undergo reorganization featuring new contacts between chromosome arms telomeres. These prominent interactions are mediated by...
ABSTRACT DNA replication often encounters obstacles like the stalled transcription machinery and R-loops. While ribonucleases DNA-RNA helicases can resolve these structures, role of chromatin remodelers remains understudied. Through a series in vitro vivo experiments, we show that remodeler SMARCAD1, which associates with active forks, is crucial for resolving nearby R-loops to maintain fork stability. SMARCAD1 directly binds via its ATPase domain replisome through N-terminus region. Both...
Heat stroke deaths are prevalent in tropical regions of the globe. Hyperthermia inhibits DNA double strand break (DSB) repair by homologous recombination (HR) pathway, however, mechanisms for this inhibition remain unclear. Here we report that hyperthermia decreases H4K16 acetylation (H4K16ac), an epigenetic modification essential genomic stability and transcription. Heat-induced reduction H4K16ac were detectable humans, Drosophila yeast, suggesting is a highly conserved response. We...
<p>Supplementary files</p>
<p>Supplementary files</p>
<div>Abstract<p>Optimal treatment of cancer requires diagnostic methods to facilitate therapy choice and prevent ineffective treatments. Direct assessment response in viable tumor specimens could fill this gap. Therefore, we designed a microfluidic platform for patient using tissue slices under precisely controlled growth conditions. The optimized Cancer-on-Chip (CoC) maintained viability sustained proliferation breast prostate 7 days. No major changes morphology or gene...
<div>Abstract<p>Optimal treatment of cancer requires diagnostic methods to facilitate therapy choice and prevent ineffective treatments. Direct assessment response in viable tumor specimens could fill this gap. Therefore, we designed a microfluidic platform for patient using tissue slices under precisely controlled growth conditions. The optimized Cancer-on-Chip (CoC) maintained viability sustained proliferation breast prostate 7 days. No major changes morphology or gene...
ABSTRACT Stalled fork protection pathway mediated by BRCA1/2 proteins is critical for replication stability that has implications in tumorigenesis. However, it unclear if additional mechanisms are required to maintain stability. We describe a novel mechanism which the chromatin remodeler SMARCAD1 stabilizes active forks essential resistance towards poisons. find loss of results toxic enrichment 53BP1 at mediates untimely dissociation PCNA via PCNA-unloader, ATAD5. Faster causes frequent...
Chemotherapeutic regimens that poison DNA replication are used for the treatment of homologous recombination (HR)-deficient cancers. We have discovered a novel mechanism by which SWI/SNF chromatin remodeler SMARCAD1 stabilizes forks is essential resistance towards poisons. find loss results in toxic enrichment 53BP1 at mediates untimely dissociation PCNA via PCNA-unloader, ATAD5. Faster causes frequent fork stalling, inefficient restart and accumulation single-stranded resulting genome...