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  • 1.
    Chen, Sa
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Expression and function of Suppressor of zeste 12 in Drosophila melanogaster2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The development of animals and plants needs a higher order of regulation of gene expression to maintain proper cell state. The mechanisms that control what, when and where a gene should (or should not) be expressed are essential for correct organism development. The Polycomb group (PcG) is a family of genes responsible for maintaining gene silencing and Suppressor of zeste 12 (Su(z)12) is one of the core components in the PcG. The gene is highly conserved in organisms ranging from plants to humans, however, the specific function is not well known. The main tasks of this thesis was to investigate the function of Su(z)12 and its expression at different stages of Drosophila development.

    In polytene chromosomes of larval salivary glands, Su(z)12 binds to about 90 specific euchromatic sites. The binding along the chromosome arms is mostly in interbands, which are the most DNA de-condensed regions. The binding sites of Su(z)12 in polytene chromosomes correlate precisely with those of the Enhancer-of-zeste (E(z)) protein, indicating that Su(z)12 mainly exists within the Polycomb Repressive Complex 2 (PRC2). However, the binding pattern does not overlap well with Histone 3 lysine 27 tri-methylations (H3K27me3), the specific chromatin mark created by PRC2. The Su(z)12 binding to chromatin is dynamically regulated during mitotic and meiotic cell division. The two different Su(z)12 isoforms: Su(z)12-A and Su(z)12-B (resulting from alternative RNA splicing), have very different expression patterns during development. Functional analyses indicate that they also have different functions he Su(z)12-B form is the main mediator of silencing. Furthermore, a neuron specific localization pattern in larval brain and a giant larval phenotype in transgenic lines reveal a potential function of Su(z)12-A in neuron development.  In some aspects the isoforms seem to be able to substitute for each other.

    The histone methyltransferase activity of PRC2 is due to the E(z) protein. However, Su(z)12 is also necessary for H3K27me3 methylation in vivo, and it is thus a core component of PRC2. Clonal over-expression of Su(z)12 in imaginal wing discs results in an increased H3K27me3 activity, indicating that Su(z)12 is a limiting factor for silencing. When PcG function is lost, target genes normally become de-repressed. The segment polarity gene engrailed, encoding a transcription factor, is a target for PRC2 silencing. However, we found that it was not activated when PRC2 function was deleted. We show that the Ultrabithorax protein, encoded by another PcG target gene, also acts as an inhibitor of engrailed and that de-regulation of this gene causes a continued repression of engrailed. The conclusion is that a gene can have several negative regulators working in parallel and that secondary effects have to be taken into consideration, when analyzing effects of mutants.

    PcG silencing affects very many cellular processes and a large quantity of knowledge is gathered on the overall mechanisms of PcG regulation. However, little is known about how individual genes are silenced and how cells “remember” their fate through cell generations.

  • 2.
    Chen, Sa
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Anna L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Tegeling, Erik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Rasmuson Lestander, Asa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    In vivo analysis of Suppressor of zeste 12´s different isoformsManuscript (Other academic)
    Abstract [en]

    Polycomb Group (PcG) genes are known to encode a large chromatin-associated family of proteins which are involved in genomic regulation of many cellular processes. Su(z)12 is a key component in PcG silencing. It is needed for three levels of methylation of histone 3 lysine 27 in vivo in Drosophila. Here, we report that Su(z)12 may exist in different isoforms and that these isoforms are spatially and temporally regulated. The biological function of the Su(z)12-A and -B isoforms seems to be very different. For instance the transgenic Su(z)12-B and the human homolog SUZ12, but not Su(z)12-A, rescue Su(z)12 mutants. Furthermore, transgenic flies over-expressing Su(z)12-B show typical homeotic transformation phenotypes, while over-expression of Su(z)12-A does not. However, the two isoforms appears to be able to substitute for each other in some aspects. During larval and pupal stages, Su(z)12-A seems to play the main role. 

  • 3.
    Chen, Sa
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rasmuson-Lestander, Åsa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Regulation of the Drosophila engrailed gene by Polycomb repressor complex 22009In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 126, no 5-6, p. 443-448Article in journal (Refereed)
    Abstract [en]

    Suppressor-of-zeste-12 (Su(z)12) is a core component of the Polycomb repressive complex 2 (PRC2), which has a methyltransferase activity directed towards lysine residues of histone 3. Mutations in Polycomb group (PcG) genes cause de-repression of homeotic genes and subsequent homeotic transformations. Another target for Polycomb silencing is the engrailed gene, which encodes a key regulator of segmentation in the early Drosophila embryo. In close proximity to the en gene is a Polycomb Response Element, but whether en is regulated by Su(z)12 is not known. In this report, we show that en is not de-repressed in Su(z)12 or Enhancer-of-zeste mutant clones in the anterior compartment of wing discs. Instead, we find that en expression is down-regulated in the posterior portion of wing discs, indicating that the PRC2 complex acts as an activator of en. Our results indicate that this is due to secondary effects, probably caused by ectopic expression of Ubx and Abd-B.

  • 4.
    Chen, Sa
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rasmuson-Lestander, Åsa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The role of Suppressor of zeste 12 in cell cycle regulationManuscript (Other academic)
    Abstract [en]

    Polycomb group (PcG) proteins control a large amount of target genes and are essential for genomic programming and differentiation. Many members in the PcG family have been shown to be upregulated in different types of cancers. Suppressor of zeste 12 (Su(z)12) is an essential component in PcG silencing and is necessary for histone 3 lysine 27 tri-methylation in vivo. To unravel a possible role of Su(z)12 in cell cycle regulation, we first investigate the localization pattern of Su(z)12 in Drosophila wildtype testes and embryos by immunohistochemical staining. We found that Su(z)12 was dynamically regulated during cell division. Further investigation of the function of Su(z)12 in cell division was done by cell number counting, apoptosis and proliferation marker staining in Su(z)12 somatic knockout clones in wing discs. The conclusion from the small wing phenotype in Su(z)12 knockout wing discs is that Su(z)12 may increase apoptosis and decrease cell proliferation rate.

  • 5. Haronikova, Lucia
    et al.
    Olivares-Illana, Vanesa
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Karakostis, Konstantinos
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic; 4Inserm U1162, Paris, France; ICCVS, University of Gdansk, Science, Gdansk, Poland.
    The p53 mRNA: an integral part of the cellular stress response2019In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, no 7, p. 3257-3271Article in journal (Refereed)
    Abstract [en]

    A large number of signalling pathways converge on p53 to induce different cellular stress responses that aim to promote cell cycle arrest and repair or, if the damage is too severe, to induce irreversible senescence or apoptosis. The differentiation of p53 activity towards specific cellular outcomes is tightly regulated via a hierarchical order of post-translational modifications and regulated protein-protein interactions. The mechanisms governing these processes provide a model for how cells optimize the genetic information for maximal diversity. The p53 mRNA also plays a role in this process and this review aims to illustrate how protein and RNA interactions throughout the p53 mRNA in response to different signalling pathways control RNA stability, translation efficiency or alternative initiation of translation. We also describe how a p53 mRNA platform shows riboswitch-like features and controls the rate of p53 synthesis, protein stability and modifications of the nascent p53 protein. A single cancer-derived synonymous mutation disrupts the folding of this platform and prevents p53 activation following DNA damage. The role of the p53 mRNA as a target for signalling pathways illustrates how mRNA sequences have co-evolved with the function of the encoded protein and sheds new light on the information hidden within mRNAs.

  • 6.
    Larsson, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Tegeling, Erik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Chen, Sa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lu, C-M
    Stief, A
    Rasmuson-Lestander, Åsa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Investigation of the two isoforms of SU(Z)12 shows difference in expressionand interaction in vitro with the core components of PRC2Manuscript (preprint) (Other academic)
  • 7. Uhrik, Lukas
    et al.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Haronikova, Lucia
    Medina-Medina, Ixaura
    Rebolloso-Gomez, Yolanda
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Vojtesek, Borivoj
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hernychova, Lenka
    Olivares-Illana, Vanesa
    Allosteric changes in HDM2 by the ATM phosphomimetic S395D mutation: implications on HDM2 function2019In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 476, p. 3401-3411Article in journal (Refereed)
    Abstract [en]

    Allosteric changes imposed by post-translational modifications regulate and differentiate the functions of proteins with intrinsic disorder regions. HDM2 is a hub protein with a large interactome and with different cellular functions. It is best known for its regulation of the p53 tumour suppressor. Under normal cellular conditions, HDM2 ubiquitinates and degrades p53 by the 26S proteasome but after DNA damage, HDM2 switches from a negative to a positive regulator of p53 by binding to p53 mRNA to promote translation of the p53 mRNA. This change in activity is governed by the ataxia telangiectasia mutated kinase via phosphorylation on serine 395 and is mimicked by the S395D phosphomimetic mutant. Here we have used different approaches to show that this event is accompanied by a specific change in the HDM2 structure that affects the HDM2 interactome, such as the N-termini HDM2-p53 protein-protein interaction. These data will give a better understanding of how HDM2 switches from a negative to a positive regulator of p53 and gain new insights into the control of the HDM2 structure and its interactome under different cellular conditions and help identify interphases as potential targets for new drug developments.

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