Publications by authors named "Marcel van Vugt"
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat mutant cancers. Although PARPi sensitivity has been attributed to homologous recombination (HR) defects, other roles of HR factors have also been linked to response to PARPi, including replication fork protection. In this study, we investigated PARPi sensitivity in ovarian cancer patient-derived xenograft (PDX) models in relation to HR proficiency and replication fork protection.
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- Long-term issues in chromatin assembly during DNA replication can significantly impact how cells maintain their epigenetic information and decide their fate.
- Researchers studied the effects of quickly removing a key protein called CAF-1, which is crucial for building chromatin, by using advanced techniques like single-cell genomics and live microscopy.
- The loss of CAF-1 slows DNA replication, makes new DNA more accessible, triggers a unique cellular response that reduces histone mRNA levels, and ultimately leads to cell-cycle arrest influenced by p53, highlighting the immediate consequences of faulty chromatin assembly.
Article Synopsis
- During DNA repair, some types of damage cause breaks in the DNA, and a special group called the Fanconi anemia (FA) core complex helps fix these breaks.
- Researchers found that two members of this complex, FANCL and Ube2T, play an important role in fixing DNA breaks even when they aren't caused by interstrand crosslinks (ICLs).
- The study showed that FANCL helps gather other repair proteins at the break sites, making it easier for the cell to fix the DNA properly.
Replication stress (RS) is a key trait of cancer cells, and a potential actionable target in cancer treatment. Accurate methods to measure RS in tumour samples are currently lacking. DNA fibre analysis has been used as a common technique to measure RS in cell lines.
View Article and Find Full Text PDFIn a human cell, thousands of replication forks simultaneously coordinate duplication of the entire genome. The rate at which this process occurs might depend on the epigenetic state of the genome and vary between, or even within, cell types. To accurately measure DNA replication speeds, we developed single-cell 5-ethynyl-2'-deoxyuridine sequencing to detect nascent replicated DNA.
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- - Overexpression of Cyclin E1 disrupts DNA replication, leading to DNA damage and instability, which forces cancer cells to rely on repair mechanisms like RAD52-mediated break-induced replication.
- - Many DNA lesions caused by Cyclin E1 during the S phase are not repaired before mitosis, resulting in mitotic DNA synthesis (MiDAS) that depends on RAD52.
- - Targeting RAD52 during mitosis can reduce the viability of Cyclin E1-overexpressing cells, and a positive link between Cyclin E1 amplification and RAD52 levels is found in breast cancer samples, highlighting RAD52’s role in maintaining genomic stability.
DNA repair through homologous recombination (HR) is of vital importance for maintaining genome stability and preventing tumorigenesis. RAD51 is the core component of HR, catalyzing the strand invasion and homology search. Here, we highlight recent findings on FIRRM and FIGNL1 as regulators of the dynamics of RAD51.
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- When BRCA1 and BRCA2 genes are mutated, they can't fix DNA breaks properly, which can lead to cancer.
- Scientists found that cells with BRCA1 mutations rely on a factor called EXO1 to fix DNA damage, making EXO1 a weak spot for these cells.
- If EXO1 is missing in BRCA1-mutated cells, they struggle to repair DNA breaks, but BRCA2-mutated cells can still manage without EXO1, suggesting that targeting EXO1 could help treat BRCA1-related cancers.
Genomic instability, as caused by oncogene-induced replication stress, can lead to the activation of inflammatory signaling, involving the cGAS-STING and JAK-STAT pathways. Inflammatory signaling has been associated with pro-tumorigenic features, but also with favorable response to treatment, including to immune checkpoint inhibition. In this study, we aim to explore relations between inflammatory signaling, markers of replication stress, and immune cell infiltration in breast cancer.
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- Homologous Recombination (HR) is a precise mechanism that repairs DNA Double-Strand Breaks (DSBs), which can occur due to various damaging factors like radiation or chemicals.
- The study identified members of the Fanconi anemia (FA) core complex, specifically FANCL and Ube2T, as key players in promoting HR at DSBs, even independent of interstrand crosslinks (ICLs).
- The findings also highlight that FANCL's activity is crucial for recruiting the nuclease CtIP to DSB sites, which is necessary for effective HR, suggesting a dual role for the FA complex in DNA repair.
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- Joint DNA molecules from DNA replication and repair can lead to ultrafine DNA bridges (UFBs) during mitosis, which hinder sister chromatid separation.
- The study highlights the importance of PICH, a DNA translocase, in resolving UFBs and identifies FIRRM as a key regulator that interacts with FIGNL1, an ATPase involved in DNA processes.
- Inhibition of FIRRM or FIGNL1 causes UFBs to form and disrupts RAD51 dynamics at replication forks, leading to DNA damage and reliance on PICH for cell survival.
Objective: In the first part of this phase II study (NCT01164995), the combination of carboplatin and adavosertib (AZD1775) was shown to be safe and effective in patients with TP53 mutated platinum-resistant ovarian cancer (PROC). Here, we present the results of an additional safety and efficacy cohort and explore predictive biomarkers for resistance and response to this combination treatment.
Methods: This is a phase II, open-label, non-randomized study.
The PSMC3IP-MND1 heterodimer promotes meiotic D loop formation before DNA strand exchange. In genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, depletion of PSMC3IP or MND1 causes sensitivity to poly (ADP-Ribose) polymerase inhibitors (PARPi) used in cancer treatment. PSMC3IP or MND1 depletion also causes ionizing radiation sensitivity.
View Article and Find Full Text PDFOncogene-induced replication stress has been recognized as a major cause of genome instability in cancer cells. Increased expression of cyclin E1 caused by amplification of the CCNE1 gene is a common cause of replication stress in various cancers. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and has been implicated in termination of the cell cycle checkpoint.
View Article and Find Full Text PDFSister chromatid exchanges (SCEs) are products of joint DNA molecule resolution, and are considered to form through homologous recombination (HR). Indeed, SCE induction upon irradiation requires the canonical HR factors BRCA1, BRCA2 and RAD51. In contrast, replication-blocking agents, including PARP inhibitors, induce SCEs independently of BRCA1, BRCA2 and RAD51.
View Article and Find Full Text PDFThe limited efficacy of immune checkpoint inhibitor treatment in triple-negative breast cancer (TNBC) patients is attributed to sparse or unresponsive tumor-infiltrating lymphocytes, but the mechanisms that lead to a therapy resistant tumor immune microenvironment are incompletely known. Here we show a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreases lymphocyte infiltration in tumors, along with immune signature remodelling.
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- Some cells have a hard time fixing dangerous breaks in their DNA, which can lead to problems like cancer!
- Normally, cells have safety checks to stop broken DNA from going into a new phase of the cell cycle, but cancer cells often ignore these checks!
- This review talks about how cancer cells deal with these DNA problems during cell division and what happens to the cell if they can't fix them!
Chromosomal instability (CIN) drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor prognosis. CIN leads to micronuclei that release DNA into the cytoplasm after rupture, which triggers activation of inflammatory signalling mediated by cGAS and STING. These two proteins are considered to be tumour suppressors as they promote apoptosis and immunosurveillance.
View Article and Find Full Text PDFOncogene-induced replication stress characterizes many aggressive cancers. Several treatments are being developed that target replication stress, however, identification of tumors with high levels of replication stress remains challenging. We describe a gene expression signature of oncogene-induced replication stress.
View Article and Find Full Text PDFGenomic instability and inflammation are intricately connected hallmark features of cancer. DNA repair defects due to BRCA1/2 mutation instigate immune signaling through the cGAS/STING pathway. The subsequent inflammatory signaling provides both tumor-suppressive as well as tumor-promoting traits.
View Article and Find Full Text PDFGenomic instability, inflammatory signaling and response to cancer immunotherapy.
Biochim Biophys Acta Rev Cancer
January 2022
Article Synopsis
- Cancer cells often have problems with their DNA and chromosomes, which can change how they grow and how they respond to treatments.
- When there's a lot of DNA leakage from the cell's nucleus, it can trigger the body's immune response to fight cancer.
- However, some cancers find ways to avoid being attacked by the immune system by shutting down this signaling.
Article Synopsis
- Scientists studied a type of brain tumor in kids called high-grade glioma that has a special gene mutation in a protein called H3.3.
- They found that this mutation might be causing problems with how DNA is copied during cell division, making it unstable.
- By using lab experiments, they showed that when this mutation is present, it leads to more mistakes in DNA copying, which could help the tumor grow.
Following DNA replication, equal amounts of chromatin proteins are distributed over sister chromatids by re-deposition of parental chromatin proteins and deposition of newly synthesized chromatin proteins. Molecular mechanisms balancing the allocation of new and old chromatin proteins remain largely unknown. Here, we studied the genome-wide distribution of new chromatin proteins relative to parental DNA template strands and replication initiation zones using the double-click-seq.
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