Publications by authors named "Nathalie van den Tempel"

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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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.

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Article Synopsis
  • - 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.
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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.
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Tumours with mutations in the BRCA1/BRCA2 genes have impaired double-stranded DNA break repair, compromised replication fork protection and increased sensitivity to replication blocking agents, a phenotype collectively known as 'BRCAness'. Tumours with a BRCAness phenotype become dependent on alternative repair pathways that are error-prone and introduce specific patterns of somatic mutations across the genome. The increasing availability of next-generation sequencing data of tumour samples has enabled identification of distinct mutational signatures associated with BRCAness.

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Oncogene-induced replication stress, for instance as a result of Cyclin E1 overexpression, causes genomic instability and has been linked to tumorigenesis. To survive high levels of replication stress, tumors depend on pathways to deal with these DNA lesions, which represent a therapeutically actionable vulnerability. We aimed to uncover the consequences of Cyclin E1 or Cdc25A overexpression on replication kinetics, mitotic progression, and the sensitivity to inhibitors of the WEE1 and ATR replication checkpoint kinases.

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The tumor suppressor BRCA2 is essential for homologous recombination (HR), replication fork stability, and DNA interstrand crosslink repair in vertebrates. We identify HSF2BP, a protein previously described as testis specific and not characterized functionally, as an interactor of BRCA2 in mouse embryonic stem cells, where the 2 proteins form a constitutive complex. HSF2BP is transcribed in all cultured human cancer cell lines tested and elevated in some tumor samples.

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The DNA damage response (DDR) is a designation for a number of pathways that protects our DNA from various damaging agents. In normal cells, the DDR is extremely important for maintaining genome integrity, but in cancer cells these mechanisms counteract therapy-induced DNA damage. Inhibition of the DDR could therefore be used to increase the efficacy of anti-cancer treatments.

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Introduction: Bladder cancer (urothelial carcinoma) is a common malignancy characterized by high recurrence rates and intense clinical follow-up, indicating the necessity for more effective therapies. Current treatment regimens include intra-vesical administration of mitomycin C (MMC) for non-muscle invasive disease and systemic cisplatin for muscle-invasive or metastatic disease. Hyperthermia, heating a tumor to 40-44°C, enhances the efficacy of these chemotherapeutics by various modes of action, one of which is inhibition of DNA repair via homologous recombination.

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Article Synopsis
  • Genomic instability, a key characteristic of cancer cells, arises from faulty DNA repair processes, such as the inactivation of the BRCA2 gene, which is critical for cellular survival but lethal in embryonic mice.
  • This study investigates the survival genes that genomically unstable cancer cells depend on, identifying a cluster of 11 cell cycle-related genes through mRNA profiling of 16,172 cancer samples.
  • Notably, the loss of TPX2 or its associated kinase Aurora-A significantly harms the viability of BRCA2-deficient cancer cells, suggesting potential therapeutic targets for treating genomically unstable cancers.
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Hyperthermia - application of supra-physiological temperatures to cells, tissues or organs - is a pleiotropic treatment that affects most aspects of cellular metabolism, but its effects on DNA are of special interest in the context of cancer research and treatment. Hyperthermia inhibits repair of various DNA lesions, including double-strand breaks (DSBs), making it a powerful radio- and chemosensitizer, with proven clinical efficacy in therapy of various types of cancer, including tumors of head and neck, bladder, breast and cervix. Among the challenges for hyperthermia-based therapies are the transient character of its effects, the technical difficulties in maintaining uniformly elevated tumor temperature and the acquisition of thermotolerance.

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Purpose: Hyperthermia (40-44 °C) effectively sensitises tumours to radiotherapy by locally altering tumour biology. One of the effects of heat at the cellular level is inhibition of DNA repair by homologous recombination via degradation of the BRCA2-protein. This suggests that hyperthermia can expand the group of patients that benefit from PARP-inhibitors, a drug exploiting homologous recombination deficiency.

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Hyperthermia has a number of biological effects that sensitize tumors to radiotherapy in the range between 40-44 °C. One of these effects is heat-induced degradation of BRCA2 that in turn causes reduced RAD51 focus formation, which results in an attenuation of DNA repair through homologous recombination. Prompted by this molecular insight into how hyperthermia attenuates homologous recombination, we now quantitatively explore time and temperature dynamics of hyperthermia on BRCA2 levels and RAD51 focus formation in cell culture models, and link this to their clonogenic survival capacity after irradiation (0-6 Gy).

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It has long been established that hyperthermia increases the therapeutic benefit of radiation and chemotherapy in cancer treatment. During the last few years there have been substantial technical improvements in the sources used to apply and measure heat, which greatly increases enthusiasm for the clinical use of hyperthermia. These advances are converging with a better understanding of the physiological and molecular effects of hyperthermia.

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  • Inherited DNA variations on the Y chromosome allow us to trace male ancestry effectively.
  • A new genotyping method has been developed to detect major Y chromosome haplogroups (A-T) and refine haplogroup O into its sublineages.
  • The introduction of assays for haplogroups E, G, I, J, and R improves lineage discrimination and helps pinpoint geographic origins, making it useful for studies in forensics, anthropology, and genealogy.
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The majority of human Y chromosomes in men from East and Southeast Asia, and a considerable proportion of Oceanian men, especially those from Remote Oceania, belong to haplogroup O, characterized by a 5-bp deletion known as M175 (rs2032678). Recent advances in Y-SNP (single-nucleotide polymorphism) discovery have substantially improved the phylogenetic resolution of haplogroup O sublineages. By taking advantage of this recent knowledge, we hereby introduce a sensitive Y-SNP multiplex genotyping assay for the dissection of haplogroup O into its most significant sublineages.

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