Joris Pothof's research while affiliated with Erasmus University Rotterdam and other places

Publications (51)

Article
Full-text available
Organs age differently, causing wide heterogeneity in multimorbidity, but underlying mechanisms are largely elusive. To investigate the basis of organ-specific ageing, we utilized progeroid repair-deficient Ercc1Δ /- mouse mutants and systematically compared at the tissue, stem cell and organoid level two organs representing ageing extremes. Ercc1Δ...
Article
Full-text available
Purpose: We investigated whether organoids can be generated from resected tumors of patients who received eight cycles of neoadjuvant FOLFIRINOX chemotherapy before surgery, and evaluated the sensitivity/resistance of these surviving cancer cells to cancer therapy. Experimental design: We generated a library of 10 PDAC organoid lines: five each...
Article
Ageing is a complex, multifaceted process leading to widespread functional decline that affects every organ and tissue, but it remains unknown whether ageing has a unifying causal mechanism or is grounded in multiple sources. Phenotypically, the ageing process is associated with a wide variety of features at the molecular, cellular and physiologica...
Article
Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Disruption of this pathway can contribute to the development of cancer and accelerate aging. Mutational characteristics of NER-deficiency may reveal important diagnostic opportunities, as tumors deficient in NER are more sensitive to c...
Article
Full-text available
Uveal melanoma (UM) is the most frequently found primary intra-ocular tumor in adults. It is a highly aggressive cancer that causes metastasis-related mortality in up to half of the patients. Many independent studies have reported somatic genetic changes associated with high metastatic risk, such as monosomy of chromosome 3 and mutations in BAP1. S...
Preprint
Full-text available
Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Deficiency in this pathway can contribute to the development of cancer and accelerate aging. In addition, NER-deficiency is an important determinant for cancer treatment outcome, as NER-deficient tumors are sensitive to cisplatin treat...
Article
Full-text available
Initiation and promoter-proximal pausing are key regulatory steps of RNA Polymerase II (Pol II) transcription. To study the in vivo dynamics of endogenous Pol II during these steps, we generated fully functional GFP-RPB1 knockin cells. GFP-RPB1 photobleaching combined with computational modeling revealed four kinetically distinct Pol II fractions a...
Article
The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether ho...
Article
Full-text available
Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1?/-) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a ‘survival response’, which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as calori...
Article
Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Resistance to therapy is a major limitation towards the cure of irresectable cancer. Cellular senescence, induced by chemotherapy and radiotherapy, can drive therapy resistance in vivo. Senescence is a tumor suppressive mechanism, but senescent cells can secrete a ran...
Article
Cancer cells that acquire radio-resistance are major problem for treatment outcome. We aimed at identifying mechanisms and networks that control ionizing radiation (IR)-resistance in prostate cancer cells. To this end, we applied to cancer cell lines an identical radiotherapy regiment as performed in the clinic, i.e. a total dose of 78 Gy in steps...
Article
Full-text available
Background: Drug resistance hampers the efficient treatment of malignancies, including advanced stage ovarian cancer, which has a 5-year survival rate of only 30 %. The molecular processes underlying resistance have been extensively studied, however, not much is known about the involvement of microRNAs. Methods: Differentially expressed microRNA...
Article
Human syndromes and mouse mutants that exhibit accelerated but bona fide aging in multiple organs and tissues have been invaluable for the identification of nine denominators of aging: telomere attrition, genome instability, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, loss of...
Article
Full-text available
Standard RNA expression profiling methods rely on enrichment steps for specific RNA classes, thereby not detecting all RNA species. For example, small and large RNAs from the same sample cannot be sequenced in a single sequence run. We designed RNAome sequencing, which is a strand-specific method to determine the expression of small and large RNAs...
Article
Full-text available
Bladder cancer has a high incidence with significant morbidity and mortality. Attenuated expression of the DNA damage response protein Xeroderma Pigmentosum complementation group C (XPC) has been described in bladder cancer. XPC plays an essential role as the main initiator and damage-detector in global genome nucleotide excision repair (NER) of UV...
Article
Full-text available
Current RNA expression profiling methods rely on enrichment steps for specific RNA classes, thereby not detecting all RNA species in an unperturbed manner. We report strand-specific RNAome sequencing that determines expression of small and large RNAs from rRNA-depleted total RNA in a single sequence run. Since current analysis pipelines cannot reli...
Article
Recent advances have identified accumulation of DNA damage as a major driver of aging. However, there are numerous kinds of DNA lesions each with their own characteristics and cellular outcome, which highly depends on cellular context: proliferation (cell cycle), differentiation, propensity for survival/death, cell condition and systemic hormonal a...
Article
The emergence of high density technologies monitoring the genome, transcriptome and proteome in relation to genotoxic stress have tremendously enhanced our knowledge on global responses and dynamics in the DNA damage response, including its relation with cancer and aging. Moreover, '-omics' technologies identified many novel factors, their post-tra...
Article
Full-text available
There is a high need to improve the assessment of, especially non-genotoxic, carcinogenic features of chemicals. We therefore explored a toxicogenomics-based approach using genome-wide microRNA and mRNA expression profiles upon short-term exposure in mice. For this, wild-type mice were exposed for seven days to three different classes of chemicals,...
Article
The DNA damage response (DDR) is activated upon DNA damage and prevents accumulation of mutations and chromosomal rearrangements, both driving carcinogenesis. Tumor cells often have defects in the DDR, which in combination with continuous cell proliferation are exploited by genotoxic cancer therapies. Most cancers, overcome initial sensitivity and...
Article
Full-text available
Dendritic cell (DC) maturation is a tightly regulated process that requires coordinated and timed developmental cues. Here we investigate whether microRNAs are involved in this process. We identify microRNAs in mouse GM-CSF-generated, monocyte-related DC (GM-DC) that are differentially expressed during both spontaneous and LPS-induced maturation an...
Article
Full-text available
MicroRNAs (miRNAs) are evolutionarily conserved non-coding RNAs of ∼22 nucleotides that regulate gene expression at the level of translation and play vital roles in hippocampal neuron development, function and plasticity. Here, we performed a systematic and in-depth analysis of miRNA expression profiles in cultured hippocampal neurons during develo...
Article
DNA damage and ageing share expression changes involving alterations in many aspects of metabolism, suppression of growth and upregulation of defence and genome maintenance systems. "Omics" technologies have permitted large-scale parallel measurements covering global cellular constituents and aided the identification of specific response pathways t...
Article
The development of drug resistance is still a major impediment for the successful treatment of cancer. This is particularly pressing in the case of advanced ovarian cancer, which has a 5-year survival rate of 30%. Ovarian cancer is treated with paclitaxel and platinum (e.g cisplatin or carboplatin) combination chemotherapy. Despite an initial high...
Article
Full-text available
Epithelial ovarian cancer is the most lethal gynecological malignancy in the Western world. A major impediment for the successful treatment is the development of drug resistance. The molecular processes that contribute to resistance have been extensively studied; however, there is not much known about regulation by microRNAs (miRNAs). We compared m...
Data
Full-text available
Table S3. Sequencing identified isomiRs from B-Cells of Centenarians and Controls.
Data
Full-text available
Table S5. Significantly over-represented GO categories of predicted targets of miRNA differentially expressed in B-Cells of Centenarians as compared to Controls.
Data
Full-text available
Table S1. Summary of read/sequence counts for miRNA analysis from lymphoblastoid cell lines from centenarians (n = 3) and controls (n = 3).
Data
Full-text available
Table S2. Complete list of known (miRBase v 9) average miRNA read counts from lymphoblastoid cells from centenarians (n = 3) and controls (n = 3). All reads present in 50% or more samples with a read number greater than 10.
Data
Full-text available
Table S4. Putative and Confirmed Targets of differentially expressed miRNAs.
Article
Full-text available
Background MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and play a critical role in development, homeostasis, and disease. Despite their demonstrated roles in age-associated pathologies, little is known about the role of miRNAs in human aging and longevity. Results We employed massively parallel sequencing technology...
Article
Full-text available
Epithelial ovarian cancer is the most lethal gynecological malignancy in the Western world. A major impediment for the successful treatment is the development of drug resistance. The molecular processes that contribute to resistance have been extensively studied; however, there is not much known about regulation by microRNAs (miRNAs). We compared m...
Article
Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Tumor cells are often characterized by a rapid cell division rate and defects in their DNA damage response, which is exploited in the clinic by the use of DNA damaging anticancer agents. Platinum-based chemotherapy (e.g. cisplatin) is used for the treatment of many different...
Article
Many carcinogenic agents such as ultra-violet light from the sun and various natural and man-made chemicals act by damaging the DNA. To deal with these potentially detrimental effects of DNA damage, cells induce a complex DNA damage response (DDR) that includes DNA repair, cell cycle checkpoints, damage tolerance systems and apoptosis. This DDR is...
Article
MicroRNA-mediated modulation of translation has been recently discovered as a new dimension in gene expression regulation. In this chapter we review how this regulation operates in time between the fast protein modification and degradation steps on the one hand and the slow transcriptional reprogramming associated with more stable changes in gene e...
Article
The 3rd US-EU Workshop on systems level understanding of DNA damage responses was held from March 30 to April 1, 2009 in Egmond aan Zee, The Netherlands. Objectives of the workshop were (1) to assess the current science of the DDR, in particular network level responses to chemotherapeutic and environmentally induced DNA damage; and (2) to establish...
Article
Full-text available
DNA damage induced by UV irradiation provokes profound changes in gene expression. Both transcriptional regulation and posttranslational modification of proteins have been known for many years, but the involvement of microRNAs in regulation of mRNA translation has been described only recently. This level of gene expression regulation appears to ope...
Article
Full-text available
DNA damage provokes DNA repair, cell-cycle regulation and apoptosis. This DNA-damage response encompasses gene-expression regulation at the transcriptional and post-translational levels. We show that cellular responses to UV-induced DNA damage are also regulated at the post-transcriptional level by microRNAs. Survival and checkpoint response after...
Article
Ionizing radiation is extremely harmful for human cells, and DNA double-strand breaks (DSBs) are considered to be the main cytotoxic lesions induced. Improper processing of DSBs contributes to tumorigenesis, and mutations in DSB response genes underlie several inherited disorders characterized by cancer predisposition. Here, we performed a comprehe...
Article
Full-text available
An RNA interference (RNAi)-based genome-wide screen was performed to detect genes that contribute to genome stability in somatic cells of Caenorhabditis elegans. We identified 61 such genes; these also affect spontaneous mutagenesis in the germ line. Their sequence suggests a role in DNA repair and/or replication, in chromatin remodeling, or in cel...
Article
Mismatch-repair-deficient mutants were initially recognized as mutation-prone derivatives of bacteria, and later mismatch repair deficiency was found to predispose humans to colon cancers (HNPCC). We generated mismatch-repair-deficient Caenorhabditis elegans by deleting the msh-6 gene and analyzed the fidelity of transmission of genetic information...

Citations

... Although most people using FOLFIRINOX were included, it may be crucial to include 5-FU for AT according to the result of this study. Recently, a basic research with 10 patient-derived PC organoids reported results in line with the overall observations in this study that the resistance to oxaliplatin and irinotecan was developed in organoids from patients who received neoadjuvant FOLFIRINOX, but 5-FU treatment responses were similar between organoids from naive and FOLFIRNOX-treated patients (30). Gemcitabine of better tolerability may be considered an alternative AT, especially for patients with poor performance, since FOLFIRINOX treatment is associated with more severe adverse events (12). ...
... Aging could also cause changes in pathways related to DNA damage response and genome stability that can negatively affect the process of transdifferentiation (Schumacher et al., 2021;Yousefzadeh et al., 2021). Microarray comparisons between iPECs from lens regeneration competent young axolotls and lens regeneration incompetent semi-adult axolotls revealed that the expression of several DNA repair genes is downregulated in older animals (Sousounis et al., 2014a). ...
... Decomposition of Signature C revealed significant contributions of SBS8, SBS18, SBS32 and SBS39 (Fig. 3d). SBS8 and SBS18 have been associated with the transcription-coupled repair of damaged guanine by ROS via nucleotide excision repair (NER) 34 and base excision repair (BER) 35 pathways, respectively, suggesting that the C > A mutations may reflect the accelerated accumulation of oxidative DNA damage that overwhelms these repair pathways. ...
... Which transcription factor is used often relies on the cell type the tumor originates from [14]. Despite the fact that all UMs arise from the uvea, high-risk UMs harbor an altered transcriptome compared to low-risk UMs [16,17]. In addition, others have shown that high-risk UMs also have an increased expression of transcription regulators [16][17][18]. ...
... Cluster 4 (purple) is dominated by mutation patterns (SBS3 and deletions with microhomology) highly characteristic for homologous recombination deficiency (23). The final cluster (orange) is predominantly characterized by the aging signatures (SBS1, SBS5, and SBS40), although some samples also show APOBEC activity (20,24,25). ...
... In turn this leads to an additional decrease in the paused Pol II, an effect most easily seen for the genes with the lowest initial level of productive elongation (Supplementary Figure S4B). It is likely that the increased dependency calculated from reduction of paused Pol II due to increased P-TEFb was relatively minor because on average only 10% of paused Pol II complexes enter productive elongation and the rest terminate with a half-life of seconds to minutes (69,82,83). A similar compensatory effect by P-TEFb on pause release was recently hypothesized following depletion of the Med 14 Mediator subunit (84). ...
... Apoptosis represents a form of programmed cell death that contributes to the elimination of excess and damaged cells from an organism without disrupting tissue and organ integrity [1,2]. It is a necessary process to ensure organ growth and development as well as maintenance of adult organ homeostasis [3]. ...
... Persistent γH2AX foci provides molecular marker of DNA damage and can accelerate aging [21]. Moreover, impaired DSB repair and accumulation of DNA lesions contribute to age-associated rise of genomic instability and age-related diseases [22][23][24]. CDKN2AIP (See figure on next page.) Fig. 7 Uncompleted DNA double-strand breaks repair and synapsis in Cdkn2aip −/− spermatocytes. ...
... Collectively, the findings of these studies suggest that the enrichment of cancer stem cells induced by PTX may be a vital reason for the decrease in drug sensitivity. It has been reported that miRNAs, such as miR-1204, 40 miR-125b, 41 and miR-634, 42 can increase sensitivity to PTX. It has also been reported that miRNAs, such as miR-489 43 and miR-210, 44 can increase the drug sensitivity of 5-FU. ...
... Persistent γH2AX foci provides molecular marker of DNA damage and can accelerate aging [21]. Moreover, impaired DSB repair and accumulation of DNA lesions contribute to age-associated rise of genomic instability and age-related diseases [22][23][24]. CDKN2AIP (See figure on next page.) Fig. 7 Uncompleted DNA double-strand breaks repair and synapsis in Cdkn2aip −/− spermatocytes. ...