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8. Regulation of caspase activation during programmed cell death

Author

Cowling, Victoria Haigh

Subjects
571.936
Abstract

Most triggers of programmed cell death or apoptosis promote cytochrome c release from the mitochondria into the cytosol which initiates the activation of a panel of pro-apoptotic caspases. Activation of caspase-8 in this pathway is not well defined but may be important because it activates Bid which promotes further cytochrome c release. A range of experimental approaches have suggested different mechanisms for caspase-8 activation in this pathway. In order to identify the proteases directly responsible for caspase-8 activation, caspase-8 cleaving activity was purified from cytochrome c activated cytosolic extracts. Caspase-6 was found to be the only soluble protease in cytochrome c activated cytosolic extracts that has significant caspase-8 cleaving activity. Furthermore, caspase-6 was sufficient to induce Bid-dependent cytochrome c releasing activity in cell extracts. Inhibition of caspase-6 activity in cells significantly inhibited caspase-8 cleavage and apoptosis, therefore establishing caspase-6 as a major activator of caspase-8 in vivo and confirming that this pathway can have a critical role in promotion of apoptosis. The intrinsic activity of caspase-6 was found to be dependent on removal of the short prodomain. The requirement for two distinct cleavage steps to activate an effector caspase may represent an effective mechanism for restriction of spontaneous caspase activation and aberrant entry into apoptosis. The caspase activites which cleave the two cleavage sites of caspase-6 were purified from cytochrome c activated cell extracts. Caspase-3 and caspase- 7 were found to have different specificities for the caspase-6 cleavage sites, despite having the same preferred peptide substrates.

Published
2002

13. The RNA cap methyltransferases RNMT and CMTR1 co-ordinate gene expression during neural differentiation.

Author

Shang Liang, Almohammed, Rajaei, and Cowling, Victoria H.

Subjects
GENE expression, RNA, RIBOSOMAL proteins, RNA regulation, GENETIC regulation
Abstract

Regulation of RNA cap formation has potent impacts on gene regulation, controlling which transcripts are expressed, processed and translated into protein. Recently, the RNA cap methyltransferases RNA guanine-7 methyltransferase (RNMT) and cap-specific mRNA (nucleoside-2’-O-)-methyltransferase 1 (CMTR1) have been found to be independently regulated during embryonic stem (ES) cell differentiation controlling the expression of overlapping and distinct protein families. During neural differentiation, RNMT is repressed and CMTR1 is up-regulated. RNMT promotes expression of the pluripotencyassociated gene products; repression of the RNMT complex (RNMT–RAM) is required for repression of these RNAs and proteins during differentiation. The predominant RNA targets of CMTR1 encode the histones and ribosomal proteins (RPs). CMTR1 up-regulation is required to maintain the expression of histones and RPs during differentiation and to maintain DNA replication, RNA translation and cell proliferation. Thus the co-ordinate regulation of RNMT and CMTR1 is required for different aspects of ES cell differentiation. In this review, we discuss the mechanisms by which RNMT and CMTR1 are independently regulated during ES cell differentiation and explore how this influences the co-ordinated gene regulation required of emerging cell lineages. [ABSTRACT FROM AUTHOR]

Published
2023
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18. sj-pdf-1-jbx-10.1177_24725552211000652 – Supplemental material for Development of a High-Throughput Screening Assay to Identify Inhibitors of the SARS-CoV-2 Guanine-N7-Methyltransferase Using RapidFire Mass Spectrometry

Author

Lesley-Anne Pearson, Green, Charlotte J., Lin, De, Alain-Pierre Petit, Gray, David W., Cowling, Victoria H., and Fordyce, Euan A. F.

Subjects
FOS: Clinical medicine, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified
Abstract

Supplemental material, sj-pdf-1-jbx-10.1177_24725552211000652 for Development of a High-Throughput Screening Assay to Identify Inhibitors of the SARS-CoV-2 Guanine-N7-Methyltransferase Using RapidFire Mass Spectrometry by Lesley-Anne Pearson, Charlotte J. Green, De Lin, Alain-Pierre Petit, David W. Gray, Victoria H. Cowling and Euan A. F. Fordyce in SLAS Discovery

Published
2021
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19. Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase

Author

Basu, Souradeep, primary, Mak, Tiffany, additional, Ulferts, Rachel, additional, Wu, Mary, additional, Deegan, Tom, additional, Fujisawa, Ryo, additional, Tan, Kang Wei, additional, Lim, Chew Theng, additional, Basier, Clovis, additional, Canal, Berta, additional, Curran, Joseph F., additional, Drury, Lucy S., additional, McClure, Allison W., additional, Roberts, Emma L., additional, Weissmann, Florian, additional, Zeisner, Theresa U., additional, Beale, Rupert, additional, Cowling, Victoria H., additional, Howell, Michael, additional, Labib, Karim, additional, and Diffley, John F.X., additional

Published
2021
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20. Upregulation of RNA cap methyltransferase RNMT drives ribosome biogenesis during T cell activation

Author

Galloway, Alison, primary, Kaskar, Aneesa, additional, Ditsova, Dimitrinka, additional, Atrih, Abdelmadjid, additional, Yoshikawa, Harunori, additional, Gomez-Moreira, Carolina, additional, Suska, Olga, additional, Warminski, Marcin, additional, Grzela, Renata, additional, Lamond, Angus I, additional, Darzynkiewicz, Edward, additional, Jemielity, Jacek, additional, and Cowling, Victoria H, additional

Published
2021
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21. Identification of SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of the nsp14 RNA Cap Methyltransferase

Author

Basu, Souradeep, primary, Mak, Tiffany, additional, Ulferts, Rachel, additional, Wu, Mary, additional, Deegan, Tom, additional, Fujisawa, Ryo, additional, Tan, Kang Wei, additional, Lim, Chew Theng, additional, Basier, Clovis, additional, Canal, Berta, additional, Curran, Joseph F., additional, Drury, Lucy, additional, McClure, Allison W., additional, Roberts, Emma L., additional, Weissmann, Florian, additional, Zeisner, Theresa U., additional, Beale, Rupert, additional, Cowling, Victoria H., additional, Howell, Michael, additional, Labib, Karim, additional, and Diffley, John F.X., additional

Published
2021
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31. Supplemental Figures from CAP-MAP: cap analysis protocol with minimal analyte processing, a rapid and sensitive approach to analysing mRNA cap structures

Author

Galloway, Alison, Abdelmadjid Atrih, Grzela, Renata, Darzynkiewicz, Edward, Ferguson, Michael A. J., and Cowling, Victoria H.

Abstract

Eukaryotic messenger RNA (mRNA) is modified by the addition of an inverted guanosine cap to the 5' triphosphate. The cap guanosine and initial transcribed nucleotides are further methylated by a series of cap methyltransferases to generate the mature cap structures which protect RNA from degradation and recruit proteins involved in RNA processing and translation. Research demonstrating that the cap methyltransferases are regulated has generated interest in determining the methylation status of the mRNA cap structures present in cells. Here, we present CAP-MAP: cap analysis protocol with minimal analyte processing, a rapid and sensitive method for detecting cap structures present in mRNA isolated from tissues or cultured cells.

Published
2020
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33. Molecular basis of RNA guanine-7 methyltransferase (RNMT) activation by RAM

Author

Varshney, Dhaval, Petit, Alain-Pierre, Bueren-Calabuig, Juan A., Jansen, Chimed, Fletcher, Dan A., Peggie, Mark, Weidlich, Simone, Scullion, Paul, Pisliakov, Andrei V., and Cowling, Victoria H.

Subjects
Models, Molecular, Binding Sites, Magnetic Resonance Spectroscopy, Protein Conformation, Protein Stability, RNA-Binding Proteins, Methyltransferases, Catalysis, Enzyme Activation, Structure-Activity Relationship, Amino Acid Substitution, Catalytic Domain, Mutation, RNA, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Protein Binding
Abstract

Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. A relatively unstructured and negatively charged RAM binds to a positively charged surface groove on RNMT, distal to the active site. This results in stabilisation of a RNMT lobe structure which co-evolved with RAM and is required for RAM binding. Structure-guided mutagenesis and molecular dynamics simulations reveal that RAM stabilises the structure and positioning of the RNMT lobe and the adjacent α-helix hinge, resulting in optimal positioning of helix A which contacts substrates in the active site. Using biophysical and biochemical approaches, we observe that RAM increases the recruitment of the methyl donor, AdoMet (S-adenosyl methionine), to RNMT. Thus we report the mechanism by which RAM allosterically activates RNMT, allowing it to function as a molecular rheostat for mRNA cap methylation.

Published
2016

34. Supplemental Figures S1 - S8 from Oncogenic PIK3CA mutations increase dependency on the mRNA cap methyltransferase, RNMT, in breast cancer cells

Author

Sianadh Dunn, Lombardi, Olivia, Radoslaw Lukoszek, and Cowling, Victoria H.

Abstract

Basic mechanisms in gene expression are currently being investigated as targets in cancer therapeutics. One such fundamental process is the addition of the cap to pre-mRNA, which recruits mediators of mRNA processing and translation initiation. Maturation of the cap involves mRNA cap guanosine N-7 methylation, catalysed by RNMT (RNA guanine-7 methyltransferase). In a panel of breast cancer cell lines, we investigated whether all are equivalently dependent on RNMT for proliferation. When cellular RNMT activity was experimentally reduced by 50%, the proliferation rate of non-transformed mammary epithelial cells was unchanged, whereas a subset of breast cancer cell lines exhibited reduced proliferation and increased apoptosis. Most of the cell lines which exhibited enhanced dependency on RNMT harboured oncogenic mutations in PIK3CA, which encodes the p110α subunit of PI3 Kα. Conversely, all cell lines insensitive to RNMT depletion expressed wild-type PIK3CA. Expression of oncogenic PIK3CA mutants, which increase PI3 K p110α activity, was sufficient to increase dependency on RNMT. Conversely, inhibition of PI3 Kα reversed dependency on RNMT, suggesting that PI3 Kα signalling is required. Collectively, these findings provide evidence to support RNMT as a therapeutic target in breast cancer and suggest that therapies targeting RNMT would be most valuable in a PIK3CA mutant background.

Published
2019
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39. The eukaryotic translation initiation factor eIF4E elevates steady-state m7G capping of coding and noncoding transcripts.

Author

Culjkovic-Kraljacic, Biljana, Skrabanek, Lucy, Revuelta, Maria V., Gasiorek, Jadwiga, Cowling, Victoria H., Cerchietti, Leandro, and Borden, Katherine L. B.

Subjects
NON-coding RNA, CELL morphology, RNA, TRANSLATIONS
Abstract

Methyl-7-guanosine (m7G) "capping" of coding and some noncoding RNAs is critical for their maturation and subsequent activity. Here, we discovered that eukaryotic translation initiation factor 4E (eIF4E), itself a cap-binding protein, drives the expression of the capping machinery and increased capping efficiency of ~100 coding and noncoding RNAs. To quantify this, we developed enzymatic (cap quantification; CapQ) and quantitative cap immunoprecipitation (CapIP) methods. The CapQ method has the further advantage that it captures information about capping status independent of the type of 5' cap, i.e., it is not restricted to informing on m7G caps. These methodological advances led to unanticipated revelations: 1) Many RNA populations are inefficiently capped at steady state (~30 to 50%), and eIF4E overexpression increased this to ~60 to 100%, depending on the RNA; 2) eIF4E physically associates with noncoding RNAs in the nucleus; and 3) approximately half of eIF4E-capping targets identified are noncoding RNAs. eIF4E's association with noncoding RNAs strongly positions it to act beyond translation. Coding and noncoding capping targets have activities that influence survival, cell morphology, and cell-to-cell interaction. Given that RNA export and translation machineries typically utilize capped RNA substrates, capping regulation provides means to titrate the protein-coding capacity of the transcriptome and, for noncoding RNAs, to regulate their activities. We also discovered a cap sensitivity element (CapSE) which conferred eIF4E-dependent capping sensitivity. Finally, we observed elevated capping for specific RNAs in high-eIF4E leukemia specimens, supporting a role for cap dysregulation in malignancy. In all, levels of capping RNAs can be regulated by eIF4E. [ABSTRACT FROM AUTHOR]

Published
2020
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42. Positioning Europe for the EPITRANSCRIPTOMICS challenge

Author

Jantsch, Michael F., primary, Quattrone, Alessandro, additional, O'Connell, Mary, additional, Helm, Mark, additional, Frye, Michaela, additional, Macias-Gonzales, Manuel, additional, Ohman, Marie, additional, Ameres, Stefan, additional, Willems, Luc, additional, Fuks, Francois, additional, Oulas, Anastasis, additional, Vanacova, Stepanka, additional, Nielsen, Henrik, additional, Bousquet-Antonelli, Cecile, additional, Motorin, Yuri, additional, Roignant, Jean-Yves, additional, Balatsos, Nikolaos, additional, Dinnyes, Andras, additional, Baranov, Pavel, additional, Kelly, Vincent, additional, Lamm, Ayelet, additional, Rechavi, Gideon, additional, Pelizzola, Mattia, additional, Liepins, Janis, additional, Holodnuka Kholodnyuk, Irina, additional, Zammit, Vanessa, additional, Ayers, Duncan, additional, Drablos, Finn, additional, Dahl, John Arne, additional, Bujnicki, Janusz, additional, Jeronimo, Carmen, additional, Almeida, Raquel, additional, Neagu, Monica, additional, Costache, Marieta, additional, Bankovic, Jasna, additional, Banovic, Bojana, additional, Kyselovic, Jan, additional, Valor, Luis Miguel, additional, Selbert, Stefan, additional, Pir, Pinar, additional, Demircan, Turan, additional, Cowling, Victoria, additional, Schäfer, Matthias, additional, Rossmanith, Walter, additional, Lafontaine, Denis, additional, David, Alexandre, additional, Carre, Clement, additional, Lyko, Frank, additional, Schaffrath, Raffael, additional, Schwartz, Schraga, additional, Verdel, Andre, additional, Klungland, Arne, additional, Purta, Elzbieta, additional, Timotijevic, Gordana, additional, Cardona, Fernando, additional, Davalos, Alberto, additional, Ballana, Ester, additional, O´Carroll, Donal, additional, Ule, Jernej, additional, and Fray, Rupert, additional

Published
2018
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43. Positioning Europe for the EPITRANSCRIPTOMICS challenge

Author

Jantsch, Michael F., Quattrone, Alessandro, O'Connell, Mary, Helm, Mark, Frye, Michaela, Macias-Gonzales, Manuel, Ohman, Marie, Ameres, Stefan, Willems, Luc, Fuks, Francois, Oulas, Anastasis, Vanacova, Stepanka, Nielsen, Henrik, Bousquet-Antonelli, Cecile, Motorin, Yuri, Roignant, Jean-Yves, Balatsos, Nikolaos, Dinnyes, Andras, Baranov, Pavel, Kelly, Vincent, Lamm, Ayelet, Rechavi, Gideon, Pelizzola, Mattia, Liepins, Janis, Kholodnyuk, Irina Holodnuka, Zammit, Vanessa, Ayers, Duncan, Drablos, Finn, Dahl, John Arne, Bujnicki, Janusz, Jeronimo, Carmen, Almeida, Raquel, Neagu, Monica, Costache, Marieta, Banković, Jasna, Banović Đeri, Bojana, Kyselovic, Jan, Valor, Luis Miguel, Selbert, Stefan, Pir, Pinar, Demircan, Turan, Cowling, Victoria, Schaefer, Matthias, Rossmanith, Walter, Lafontaine, Denis, David, Alexandre, Carre, Clement, Lyko, Frank, Schaffrath, Raffael, Schwartz, Schraga, Verdel, Andre, Klungland, Arne, Purta, Elzbieta, Timotijević, Gordana, Cardona, Fernando, Davalos, Alberto, Ballana, Ester, O'Carroll, Donal, Ule, Jernej, Fray, Rupert, Jantsch, Michael F., Quattrone, Alessandro, O'Connell, Mary, Helm, Mark, Frye, Michaela, Macias-Gonzales, Manuel, Ohman, Marie, Ameres, Stefan, Willems, Luc, Fuks, Francois, Oulas, Anastasis, Vanacova, Stepanka, Nielsen, Henrik, Bousquet-Antonelli, Cecile, Motorin, Yuri, Roignant, Jean-Yves, Balatsos, Nikolaos, Dinnyes, Andras, Baranov, Pavel, Kelly, Vincent, Lamm, Ayelet, Rechavi, Gideon, Pelizzola, Mattia, Liepins, Janis, Kholodnyuk, Irina Holodnuka, Zammit, Vanessa, Ayers, Duncan, Drablos, Finn, Dahl, John Arne, Bujnicki, Janusz, Jeronimo, Carmen, Almeida, Raquel, Neagu, Monica, Costache, Marieta, Banković, Jasna, Banović Đeri, Bojana, Kyselovic, Jan, Valor, Luis Miguel, Selbert, Stefan, Pir, Pinar, Demircan, Turan, Cowling, Victoria, Schaefer, Matthias, Rossmanith, Walter, Lafontaine, Denis, David, Alexandre, Carre, Clement, Lyko, Frank, Schaffrath, Raffael, Schwartz, Schraga, Verdel, Andre, Klungland, Arne, Purta, Elzbieta, Timotijević, Gordana, Cardona, Fernando, Davalos, Alberto, Ballana, Ester, O'Carroll, Donal, Ule, Jernej, and Fray, Rupert

Abstract

The genetic alphabet consists of the four letters: C, A, G, and T in DNA and C,A,G, and U in RNA. Triplets of these four letters jointly encode 20 different amino acids out of which proteins of all organisms are built. This system is universal and is found in all kingdoms of life. However, bases in DNA and RNA can be chemically modified. In DNA, around 10 different modifications are known, and those have been studied intensively over the past 20years. Scientific studies on DNA modifications and proteins that recognize them gave rise to the large field of epigenetic and epigenomic research. The outcome of this intense research field is the discovery that development, ageing, and stem-cell dependent regeneration but also several diseases including cancer are largely controlled by the epigenetic state of cells. Consequently, this research has already led to the first FDA approved drugs that exploit the gained knowledge to combat disease. In recent years, the similar to 150 modifications found in RNA have come to the focus of intense research. Here we provide a perspective on necessary and expected developments in the fast expanding area of RNA modifications, termed epitranscriptomics.

Published
2018

44. Positioning Europe for the EPITRANSCRIPTOMICS challenge

Author

Jantsch, Michael F, Quattrone, Alessandro, O'Connell, Mary, Helm, Mark, Frye, Michaela, Macias-Gonzales, Manuel, Ohman, Marie, Ameres, Stefan, Willems, Luc, Fuks, Francois, Oulas, Anastasis, Vanacova, Stepanka, Nielsen, Henrik, Bousquet-Antonelli, Cecile, Motorin, Yuri, Roignant, Jean-Yves, Balatsos, Nikolaos, Dinnyes, Andras, Baranov, Pavel, Kelly, Vincent, Lamm, Ayelet, Rechavi, Gideon, Pelizzola, Mattia, Liepins, Janis, Holodnuka Kholodnyuk, Irina, Zammit, Vanessa, Ayers, Duncan, Drablos, Finn, Dahl, John Arne, Bujnicki, Janusz, Jeronimo, Carmen, Almeida, Raquel, Neagu, Monica, Costache, Marieta, Bankovic, Jasna, Banovic, Bojana, Kyselovic, Jan, Valor, Luis Miguel, Selbert, Stefan, Pir, Pinar, Demircan, Turan, Cowling, Victoria, Schäfer, Matthias, Rossmanith, Walter, Lafontaine, Denis, David, Alexandre, Carre, Clement, Lyko, Frank, Schaffrath, Raffael, Schwartz, Schraga, Verdel, Andre, Klungland, Arne, Purta, Elzbieta, Timotijevic, Gordana, Cardona, Fernando, Davalos, Alberto, Ballana, Ester, O Carroll, Donal, Ule, Jernej, Fray, Rupert, Jantsch, Michael F, Quattrone, Alessandro, O'Connell, Mary, Helm, Mark, Frye, Michaela, Macias-Gonzales, Manuel, Ohman, Marie, Ameres, Stefan, Willems, Luc, Fuks, Francois, Oulas, Anastasis, Vanacova, Stepanka, Nielsen, Henrik, Bousquet-Antonelli, Cecile, Motorin, Yuri, Roignant, Jean-Yves, Balatsos, Nikolaos, Dinnyes, Andras, Baranov, Pavel, Kelly, Vincent, Lamm, Ayelet, Rechavi, Gideon, Pelizzola, Mattia, Liepins, Janis, Holodnuka Kholodnyuk, Irina, Zammit, Vanessa, Ayers, Duncan, Drablos, Finn, Dahl, John Arne, Bujnicki, Janusz, Jeronimo, Carmen, Almeida, Raquel, Neagu, Monica, Costache, Marieta, Bankovic, Jasna, Banovic, Bojana, Kyselovic, Jan, Valor, Luis Miguel, Selbert, Stefan, Pir, Pinar, Demircan, Turan, Cowling, Victoria, Schäfer, Matthias, Rossmanith, Walter, Lafontaine, Denis, David, Alexandre, Carre, Clement, Lyko, Frank, Schaffrath, Raffael, Schwartz, Schraga, Verdel, Andre, Klungland, Arne, Purta, Elzbieta, Timotijevic, Gordana, Cardona, Fernando, Davalos, Alberto, Ballana, Ester, O Carroll, Donal, Ule, Jernej, and Fray, Rupert

Abstract

The genetic alphabet consists of the four letters: C, A, G, and T in DNA and C,A,G, and U in RNA. Triplets of these four letters jointly encode 20 different amino acids out of which proteins of all organisms are built. This system is universal and is found in all kingdoms of life. However, bases in DNA and RNA can be chemically modified. In DNA, around 10 different modifications are known, and those have been studied intensively over the past 20 years. Scientific studies on DNA modifications and proteins that recognize them gave rise to the large field of epigenetic and epigenomic research. The outcome of this intense research field is the discovery that development, ageing, and stem-cell dependent regeneration but also several diseases including cancer are largely controlled by the epigenetic state of cells. Consequently, this research has already led to the first FDA approved drugs that exploit the gained knowledge to combat disease. In recent years, the ~150 modifications found in RNA have come to the focus of intense research. Here we provide a perspective on necessary and expected developments in the fast expanding area of RNA modifications, termed epitranscriptomics.

Published
2018

45. Positioning Europe for the EPITRANSCRIPTOMICS challenge.

Author

Jantsch, Michael MF, Quattrone, Alessandro, O'Connell, Mary, Helm, Mark, Frye, Michaela, Macias-Gonzales, Manuel, Ohman, Marie, Ameres, Stefan, Willems, Lucas, Fuks, François, Oulas, Anastasis, Vanacova, Stepanka, Nielsen, Henrik, Bousquet-Antonelli, C, Motorin, Yuri, Roignant, Jean-Yves, Balatsos, Nikolaos, Dinnyes, Andras, Baranov, Pavel, Kelly, Vincent, Lamm, Ayelet, Rechavi, Gideon, Pelizzola, Mattia, Liepins, Janis, Holodnuka Kholodnyuk, Irina, Zammit, Vanessa, Ayers, Duncan, Drablos, Finn, Dahl, John Arne, Bujnicki, Janusz Marek, Jeronimo, Carmen, Almeida, Raquel, Neagu, Monica, Costache, Marieta, Bankovic, Jasna, Banovic, Bojana, Kyselovic, Jan, Valor, Luis Miguel, Selbert, Stefan, Pir, Pinar, Demircan, Turan, Cowling, Victoria, Schäfer, Matthias, Rossmanith, Walter, Lafontaine, Denis, David, Alexandre, Carre, Clement, Lyko, Frank, Schaffrath, Raffael, Schwartz, Schraga, Verdel, Andre, Klungland, Arne, Purta, Elzbieta, Timotijevic, Gordana, Cardona, F., Davalos, Alberto, Ballana, Ester, O Carroll, Donal, Ule, Jernej, Fray, Rupert, Jantsch, Michael MF, Quattrone, Alessandro, O'Connell, Mary, Helm, Mark, Frye, Michaela, Macias-Gonzales, Manuel, Ohman, Marie, Ameres, Stefan, Willems, Lucas, Fuks, François, Oulas, Anastasis, Vanacova, Stepanka, Nielsen, Henrik, Bousquet-Antonelli, C, Motorin, Yuri, Roignant, Jean-Yves, Balatsos, Nikolaos, Dinnyes, Andras, Baranov, Pavel, Kelly, Vincent, Lamm, Ayelet, Rechavi, Gideon, Pelizzola, Mattia, Liepins, Janis, Holodnuka Kholodnyuk, Irina, Zammit, Vanessa, Ayers, Duncan, Drablos, Finn, Dahl, John Arne, Bujnicki, Janusz Marek, Jeronimo, Carmen, Almeida, Raquel, Neagu, Monica, Costache, Marieta, Bankovic, Jasna, Banovic, Bojana, Kyselovic, Jan, Valor, Luis Miguel, Selbert, Stefan, Pir, Pinar, Demircan, Turan, Cowling, Victoria, Schäfer, Matthias, Rossmanith, Walter, Lafontaine, Denis, David, Alexandre, Carre, Clement, Lyko, Frank, Schaffrath, Raffael, Schwartz, Schraga, Verdel, Andre, Klungland, Arne, Purta, Elzbieta, Timotijevic, Gordana, Cardona, F., Davalos, Alberto, Ballana, Ester, O Carroll, Donal, Ule, Jernej, and Fray, Rupert

Abstract

The genetic alphabet consists of the four letters: C, A, G, and T in DNA and C,A,G, and U in RNA. Triplets of these four letters jointly encode 20 different amino acids out of which proteins of all organisms are built. This system is universal and is found in all kingdoms of life. However, bases in DNA and RNA can be chemically modified. In DNA, around 10 different modifications are known, and those have been studied intensively over the past 20 years. Scientific studies on DNA modifications and proteins that recognize them gave rise to the large field of epigenetic and epigenomic research. The outcome of this intense research field is the discovery that development, ageing, and stem-cell dependent regeneration but also several diseases including cancer are largely controlled by the epigenetic state of cells. Consequently, this research has already led to the first FDA approved drugs that exploit the gained knowledge to combat disease. In recent years, the ~150 modifications found in RNA have come to the focus of intense research. Here we provide a perspective on necessary and expected developments in the fast expanding area of RNA modifications, termed epitranscriptomics., SCOPUS: no.j, info:eu-repo/semantics/published

Published
2018

48. SINE transcription by RNA polymerase III is suppressed by histone methylation but not DNA methylation

Author

Varshney, Dhaval, Vavrova-Anderson, Jana, Oler, Andrew J., Cowling, Victoria H., Cairns, Bradley R., and White, Robert J.

Subjects
behavioral disciplines and activities, psychological phenomena and processes
Abstract

Short interspersed nuclear elements (SINEs), such as Alu, spread by retrotransposition, which requires their transcripts to be copied into DNA and then inserted into new chromosomal sites. This can lead to genetic damage through insertional mutagenesis and chromosomal rearrangements between non-allelic SINEs at distinct loci. SINE DNA is heavily methylated and this was thought to suppress its accessibility and transcription, thereby protecting against retrotransposition. Here we provide several lines of evidence that methylated SINE DNA is occupied by RNA polymerase III, including the use of high-throughput bisulphite sequencing of ChIP DNA. We find that loss of DNA methylation has little effect on accessibility of SINEs to transcription machinery or their expression in vivo. In contrast, a histone methyltransferase inhibitor selectively promotes SINE expression and occupancy by RNA polymerase III. The data suggest that methylation of histones rather than DNA plays a dominant role in suppressing SINE transcription.

Published
2015

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