Sigrid Swagemakers
Erasmus University Rotterdam
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Sigrid Swagemakers.
Cell | 1997
Jeroen Essers; Rudolf W. Hendriks; Sigrid Swagemakers; Christine Troelstra; Jan de Wit; D. Bootsma; Jan H.J. Hoeijmakers; Roland Kanaar
Double-strand DNA break (DSB) repair by homologous recombination occurs through the RAD52 pathway in Saccharomyces cerevisiae. Its biological importance is underscored by the conservation of many RAD52 pathway genes, including RAD54, from fungi to humans. We have analyzed the phenotype of mouse RAD54-/- (mRAD54-/-) cells. Consistent with a DSB repair defect, these cells are sensitive to ionizing radiation, mitomycin C, and methyl methanesulfonate, but not to ultraviolet light. Gene targeting experiments demonstrate that homologous recombination in mRAD54-/- cells is reduced compared to wild-type cells. These results imply that, besides DNA end-joining mediated by DNA-dependent protein kinase, homologous recombination contributes to the repair of DSBs in mammalian cells. Furthermore, we show that mRAD54-/- mice are viable and exhibit apparently normal V(D)J and immunoglobulin class-switch recombination. Thus, mRAD54 is not required for the recombination processes that generate functional immunoglobulin and T cell receptor genes.
The EMBO Journal | 2000
Jeroen Essers; Harry van Steeg; Jan de Wit; Sigrid Swagemakers; Marcel Vermeij; Jan H.J. Hoeijmakers; Roland Kanaar
Ionizing radiation and interstrand DNA crosslinking compounds provide important treatments against cancer due to their extreme genotoxicity for proliferating cells. Both the efficacies of such treatments and the mutagenic potential of these agents are modulated by the ability of cells to repair the inflicted DNA damage. Here we demonstrate that homologous recombination‐deficient mRAD54−/− mice are hypersensitive to ionizing radiation at the embryonic but, unexpectedly, not at the adult stage. However, at the adult stage mRAD54 deficiency dramatically aggravates the ionizing radiation sensitivity of severe combined immune deficiency (scid) mice that are impaired in DNA double‐strand break repair through DNA end‐joining. In contrast, regardless of developmental stage, mRAD54−/− mice are hypersensitive to the interstrand DNA crosslinking compound mitomycin C. These results demonstrate that the two major DNA double‐strand break repair pathways in mammals have overlapping as well as specialized roles, and that the relative contribution of these pathways towards repair of ionizing radiation‐induced DNA damage changes during development of the animal.
Current Biology | 1996
Roland Kanaar; Christine Troelstra; Sigrid Swagemakers; Jeroen Essers; Bep Smit; Jan Huib Franssen; Olga Bezzubova; Jean Marie Buerstedde; Beate Clever; Wolf Dietrich Heyer; Jan H.J. Hoeijmakers
BACKGROUND Homologous recombination is of eminent importance both in germ cells, to generate genetic diversity during meiosis, and in somatic cells, to safeguard DNA from genotoxic damage. The genetically well-defined RAD52 pathway is required for these processes in the yeast Saccharomyces cerevisiae. Genes similar to those in the RAD52 group have been identified in mammals. It is not known whether this conservation of primary sequence extends to conservation of function. RESULTS Here we report the isolation of cDNAs encoding a human and a mouse homolog of RAD54. The human (hHR54) and mouse (mHR54) proteins were 48% identical to Rad54 and belonged to the SNF2/SW12 family, which is characterized by amino-acid motifs found in DNA-dependent ATPases. The hHR54 gene was mapped to chromosome 1p32, and the hHR54 protein was located in the nucleus. We found that the levels of hHR54 mRNA increased in late G1 phase, as has been found for RAD54 mRNA. The level of mHR54 mRNA was elevated in organs of germ cell and lymphoid development and increased mHR54 expression correlated with the meiotic phase of spermatogenesis. The hHR54 cDNA could partially complement the methyl methanesulfonate-sensitive phenotype of S. cerevisiae rad54 delta cells. CONCLUSIONS The tissue-specific expression of mHR54 is consistent with a role for the gene in recombination. The complementation experiments show that the DNA repair function of Rad54 is conserved from yeast to humans. Our findings underscore the fundamental importance of DNA repair pathways: even though they are complex and involve multiple proteins, they seem to be functionally conserved throughout the eukaryotic kingdom.
The FASEB Journal | 2007
Marco Eijken; Sigrid Swagemakers; M. Koedam; Cobie Steenbergen; Pieter Derkx; André G. Uitterlinden; Peter J. van der Spek; Jenny A. Visser; Frank H. de Jong; Huibert A. P. Pols; Johannes P.T.M. van Leeuwen
Bone quality is an important determinant of osteoporosis, and proper osteoblast differentiation plays an important role in the control and maintenance of bone quality. We investigated the impact of activin signaling on human osteoblast differentiation, extracellular matrix formation, and mineralization. Ac‐tivins belong to the transforming growth factor‐β su‐perfamily and activin A treatment strongly inhibited mineralization in osteoblast cultures, whereas the ac‐tivin antagonist follistatin increased mineralization. Os‐teoblasts produced activin A and follistatin in a differentiation‐dependent manner, leading to autocrine regulation of extracellular matrix formation and mineralization. In addition, mineralization in a vascular smooth muscle cell‐based model for pathological calcification was inhibited. Comparative activin A and fol‐listatin gene expression profiling showed that activin signaling changes the expression of a specific range of extracellular matrix proteins prior to the onset of mineralization, leading to a matrix composition with reduced or no mineralizing capacity. These findings demonstrate the regulation of osteoblast differentiation and matrix mineralization by the activin A‐follista‐tin system, providing the possibility to control bone quality as well as pathological calcifications such as atherosclerosis by using activin A, follistatin, or analogs thereof.—Eijken M., Swagemakers, S., Koedam, M., Steenbergen, C., Derkx, P., Uitterlinden, A. G., van der Spek P. J., Visser, J. A., de Jong F. H., Pols, H. A. P., van Leeuwen J. P. T. M. The activin A‐follistatin system: potent regulator of human extracellular matrix mineralization. FASEB J. 21, 2949–2960 (2007)
Nature Genetics | 2010
Abbas M Solouki; Virginie J. M. Verhoeven; Cornelia M. van Duijn; Annemieke J. M. H. Verkerk; M. Kamran Ikram; Pirro G. Hysi; Dominiek D. G. Despriet; Leonieke M. E. van Koolwijk; Lintje Ho; Wishal D. Ramdas; Monika A. Czudowska; Robert W. A. M. Kuijpers; Najaf Amin; Maksim Struchalin; Yurii S. Aulchenko; Gabriel van Rij; Frans C C Riemslag; Terri L. Young; David A. Mackey; Tim D. Spector; Theo G. M. F. Gorgels; Jacqueline J. M. Willemse-Assink; Aaron Isaacs; Rogier Kramer; Sigrid Swagemakers; Arthur A. B. Bergen; Andy A L J van Oosterhout; Ben A. Oostra; Fernando Rivadeneira; André G. Uitterlinden
Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10−14). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16–1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42–2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.
Journal of Biological Chemistry | 1998
Sigrid Swagemakers; Jeroen Essers; Jan de Wit; Jan H.J. Hoeijmakers; Roland Kanaar
DNA double-strand break repair through theRAD52 homologous recombination pathway in the yeastSaccharomyces cerevisiae requires, among others, theRAD51, RAD52, and RAD54 genes. The biological importance of homologous recombination is underscored by the conservation of the RAD52 pathway from fungi to humans. The critical roles of the RAD52 group proteins in the early steps of recombination, the search for DNA homology and strand exchange, are now becoming apparent. Here, we report the purification of the human Rad54 protein. We showed that human Rad54 has ATPase activity that is absolutely dependent on double-stranded DNA. Unexpectedly, the ATPase activity appeared not absolutely required for the DNA repair function of human Rad54 in vivo. Despite the presence of amino acid sequence motifs that are conserved in a large family of DNA helicases, no helicase activity of human Rad54 was observed on a variety of different DNA substrates. Possible functions of human Rad54 in homologous recombination that couple the energy gained from ATP hydrolysis to translocation along DNA, rather than disruption of base pairing, are discussed.
American Journal of Human Genetics | 2009
Annemieke J. M. H. Verkerk; Rachel Schot; Belinda Dumee; Karlijn Schellekens; Sigrid Swagemakers; Aida M. Bertoli-Avella; Maarten H. Lequin; Jeroen Dudink; Paul Govaert; A.L. van Zwol; Jennifer Hirst; Marja W. Wessels; Coriene E. Catsman-Berrevoets; Frans W. Verheijen; Esther de Graaff; Irenaeus F.M. de Coo; Johan M. Kros; Rob Willemsen; Patrick J. Willems; Peter J. van der Spek; Grazia M.S. Mancini
Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years. Brain lesions were studied by diffusion tensor MR tractography. Homozygosity mapping with SNPs was performed for identification of the chromosomal locus for the disease. In the 14 Mb candidate region on chromosome 7q22, RNA expression profiling was used for selecting among the 203 genes in the area. In postmortem brain tissue available from one patient, histology and immunohistochemistry were performed. Disease course and imaging were mostly reminiscent of hypoxic-ischemic tetraplegic cerebral palsy, with neuroaxonal degeneration and white matter loss. In all five patients, a donor splice site pathogenic mutation in intron 14 of the AP4M1 gene (c.1137+1G-->T), was identified. AP4M1, encoding for the mu subunit of the adaptor protein complex-4, is involved in intracellular trafficking of glutamate receptors. Aberrant GluRdelta2 glutamate receptor localization and dendritic spine morphology were observed in the postmortem brain specimen. This disease entity, which we refer to as congenital spastic tetraplegia (CST), is therefore a genetic model for congenital cerebral palsy with evidence for neuroaxonal damage and glutamate receptor abnormality, mimicking perinatally acquired hypoxic-ischemic white matter injury.
PLOS ONE | 2010
Patric J. D. Delhanty; Yuxiang Sun; Jenny A. Visser; Anke van Kerkwijk; Martin Huisman; Wilfred van IJcken; Sigrid Swagemakers; Roy G. Smith; Axel P. N. Themmen; Aart-Jan van der Lely
Background There is increasing evidence that unacylated ghrelin (UAG) improves insulin sensitivity and glucose homeostasis; however, the mechanism for this activity is not fully understood since a UAG receptor has not been discovered. Methodology/Principal Findings To assess potential mechanisms of UAG action in vivo, we examined rapid effects of UAG on genome-wide expression patterns in fat, muscle and liver of growth hormone secretagogue receptor (GHSR)-ablated mice using microarrays. Expression data were analyzed using Ingenuity Pathways Analysis and Gene Set Enrichment Analysis. Regulation of subsets of these genes was verified by quantitative PCR in an independent experiment. UAG acutely regulated clusters of genes involved in glucose and lipid metabolism in all three tissues, consistent with enhancement of insulin sensitivity. Conclusions/Significance Fat, muscle and liver are central to the control of lipid and glucose homeostasis. UAG rapidly modulates the expression of metabolically important genes in these tissues in GHSR-deleted mice indicating a direct, GHSR-independent, action of UAG to improve insulin sensitivity and metabolic profile.
PLOS Genetics | 2008
Daan Noordermeer; Miguel R. Branco; Erik Splinter; Petra Klous; Wilfred van IJcken; Sigrid Swagemakers; Manousos Koutsourakis; Peter J. van der Spek; Ana Pombo; Wouter de Laat
The activity of locus control regions (LCR) has been correlated with chromatin decondensation, spreading of active chromatin marks, locus repositioning away from its chromosome territory (CT), increased association with transcription factories, and long-range interactions via chromatin looping. To investigate the relative importance of these events in the regulation of gene expression, we targeted the human β-globin LCR in two opposite orientations to a gene-dense region in the mouse genome containing mostly housekeeping genes. We found that each oppositely oriented LCR influenced gene expression on both sides of the integration site and over a maximum distance of 150 kilobases. A subset of genes was transcriptionally enhanced, some of which in an LCR orientation-dependent manner. The locus resides mostly at the edge of its CT and integration of the LCR in either orientation caused a more frequent positioning of the locus away from its CT. Locus association with transcription factories increased moderately, both for loci at the edge and outside of the CT. These results show that nuclear repositioning is not sufficient to increase transcription of any given gene in this region. We identified long-range interactions between the LCR and two upregulated genes and propose that LCR-gene contacts via chromatin looping determine which genes are transcriptionally enhanced.
The Journal of Clinical Endocrinology and Metabolism | 2009
W. Edward Visser; Sigrid Swagemakers; Zeliha Ozgur; Eleonora P. M. Corssmit; Jacobus Burggraaf; Wilfred van IJcken; Peter J. van der Spek; Johannes W. A. Smit; Theo J. Visser
CONTEXT Skeletal muscle is an important target tissue for thyroid hormone (TH). It is currently unknown which genes are regulated by physiological TH levels. OBJECTIVE We examined the effects of l-thyroxine on human skeletal muscle transcriptome. DESIGN Microarray analysis of transcript levels was performed using skeletal muscle biopsies from patients under euthyroid and hypothyroid conditions. SETTING The study was conducted in a university hospital laboratory. PATIENTS We studied skeletal muscle obtained from 10 thyroidectomized patients with differentiated thyroid carcinoma on and after 4 wk off L-thyroxine replacement. MEAN OUTCOME MEASURES Gene expression changes were measured using microarrays. Results were analyzed using dedicated statistical methods. RESULTS We detected 607 differentially expressed genes on L-thyroxine treatment, of which approximately 60% were positively and approximately 40% were negatively regulated. Representative genes were validated by quantitative PCR. Genes involved in energy and fuel metabolism were overrepresented among the up-regulated genes, of which a large number were newly associated with thyroid state. L-thyroxine therapy induced a large down-regulation of the primary transcripts of the noncoding microRNA pair miR-206/miR-133b. CONCLUSION We demonstrated that physiological levels of TH regulate a myriad of genes in human skeletal muscle. The identification of novel putatively TH-responsive genes may provide the molecular basis of clinical effects in subjects with different TH status. The observation that TH regulates microRNAs reveals a new layer of complexity by which TH influences cellular processes.