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Analysis of Genome Instability Using Genomic and Bioinformatic Approaches FACULTY OF SCIENCE Analysis of genome instability using genomic and bioinformatic approaches Ph.D. Thesis Kateřina Havlová Supervisor: prof. RNDr. Jiří Fajkus, CSc. Laboratory of Functional Genomics and Proteomics Brno 2020 Bibliographic Entry Author: Mgr. Kateřina Havlová Faculty of Science, Masaryk University National Centre for Biomolecular Research Functional Genomics and Proteomics Central European Institute of Technology, MU Mendel Centre for Plant Genomics and Proteomics Analysis of genome instability using genomic and Title of Thesis: bioinformatic approaches Degree programme: Genomics and proteomics Supervisor: prof. RNDr. Jiří Fajkus, CSc. Academic Year: 2019/2020 Number of Pages: 80+33 Keywords: rDNA; ribosomal DNA; ribosomal DNA intergenic spacer; chromatin; Arabidopsis thaliana; Chromatin Assembly factor 1; Physcomitrella patens; G-quadruplex Bibliografický záznam Autor: Mgr. Kateřina Havlová Přírodovědecká fakulta, Masarykova univerzita Národní centrum pro výzkum biomolekul Funkční genomika a proteomika Středoevropský technologický institut, MU Mendelovo centrum genomiky a proteomiky rostlin Analýza nestability genomu pomocí genomických a Název práce: bioinformatických přístupů Studijní program: Genomika a proteomika Vedoucí práce: prof. RNDr. Jiří Fajkus, CSc. Akademický rok: 2019/2020 Počet stran: 80+33 Klíčová slova: rDNA; ribosomální DNA; mezerník ribosomální DNA; chromatin; Arabidopsis thaliana; Chromatin Assembly factor 1; Physcomitrella patens; G-kvadruplex Abstract Ribosomal RNA genes (rDNA) are the most abundant and utilized genes in eukaryotes. They compose a vast portion of the genome and they are involved in the maintenance of the genome-wide chromatin structure. This thesis focuses on rDNA in two different model species – Arabidopsis thaliana and Physcomitrella patens. Firstly, we present here the detailed characterisation of the variability in the sequence of Arabidopsis intergenic spacer (IGS), the regulatory region separating each two copies of rRNA genes. We present a new variant in the 3’ETS region of pre-rRNA, and the preferential association of 3’ETS variants with specific IGS arrangements. Next, we mapped the IGS variant rearrangements in Arabidopsis plants which underwent rDNA loss and subsequent rDNA recovery (plants with dysfunctional histone chaperone CAF1 and plants with restored CAF1 function, respectively). Overall, CAF1-deficient plants show less variability than wild-type plants. We have observed the selective loss of some IGS variants and sporadic generation of new IGS variants. In plants with restored CAF1 function, the spectrum of IGS variants resembles that of their parental mutants, suggesting that the rDNA recovery occurs through a relatively precise DNA synthesis-dependent homologous recombination mechanism. Secondly, we present a computational analysis of rDNA sequence in Physcomitrella patens which support the hypothesis that G-quadruplex structures substantially contribute to the rDNA instability observed in Physcomitrella with dysfunctional quadruplex-unwinding helicase RTEL1. This is consistent with the ability of RTEL1 to resolve G-quadruplex structures during replication. Abstrakt Geny ribosomální RNA (rDNA) jsou nejvíce zastoupené a vytížené geny u eukaryot. Zabírají velkou část genomu a podílejí se na udržení struktury chromatinu celého genomu. Tato práce se zaměřuje na rDNA dvou rozdílných modelových druhů – Arabidopsis thaliana a Physcomitrella patens. Nejprve zde prezentujeme detailní popis variability v sekvenci genového mezerníku (IGS) u Arabidopsis, což je regulační úsek oddělující každé dvě kopie genů rRNA. Prezentujeme novou variantu v 3’ETS oblasti pre-rRNA a preferenční spojení 3’ETS variant s jejich specifickou IGS stavbou. Dále jsme mapovali přestavby variant IGS u rostlin Arabidopsis, které prodělaly ztrátu rDNA a následné obnovení rDNA (jedná se o rostliny s nefunkčním histonovým chaperonem CAF1 a rostliny s obnovenou funkcí CAF1). Celkově CAF1-deficientní rostliny vykazují menší variabilitu než rostliny wild-type. Pozorovali jsme selektivní ztrátu některých variant IGS a zřídkavé vytvoření nových variant IGS. U rostlin s obnovenou funkcí CAF1 je spektrum variant IGS podobné spektru, které bylo u jejich rodičovských mutantů, což naznačuje, že obnovení rDNA u těchto rostlin probíhá relativně přesným mechanismem homologní rekombinace závislým na syntéze DNA. Následně prezentujeme výpočetní analýzu na sekvenci rDNA u Physcomitrella patens, která podporuje hypotézu, že struktury G-kvadruplexů významně přispívají k nestabilitě rDNA, která byla pozorovaná v případě nefunkční helikázy RTEL1. To je v souladu se schopností RTEL1 rozvolňovat G-kvadruplexy během replikace. Acknowledgements Here I would like to thank my supervisor prof. RNDr. Jiří Fajkus CSc. and my consultant Mgr. Martina Dvořáčková, PhD. for the expert leading and the invaluable and kind guidance throughout my studies. I am also grateful to all colleagues from the Laboratory of Functional Genomics and Proteomics for their help and friendship. I wish to acknowledge the support of my loving family, especially my husband and my parents, who always believed in me and did their best so I could finish this thesis. This work was supported by ERDF ([project SYMBIT, reg. no. CZ.02.1.01/0.0/0.0/15 003/0000477]). Statement I hereby declare that I worked on this thesis independently and that I used only the literature listed in bibliography. Brno, 2020 ……………………………… Kateřina Havlová Original publications and the author’s contribution The thesis is based on two publications to which the author contributed. Publication 1 (Attachment 1) Havlová K., Dvořáčková M., Peiro R., Abia D., Mozgová I., Vansáčová L., Gutierrez C. and Fajkus J. (2016). Variation of 45S rDNA intergenic spacers in Arabidopsis thaliana. Plant Mol Biol. doi:10.1007/s11103-016-0524-1 The author contributed to this publication by performing the experiments: optimization of cloning, sequencing of the clones, and optimization of the samples for Pacific Biosciences sequencing. The author also did the sequence data analysis and participated in interpretation of all the results presented in the publication. Finally, the author participated in writing the manuscript. Publication 2 (Attachment 2) Goffová I., Vágnerová R., Peška V., Franěk M., Havlová K., Holá M., Zachová D., Fojtová M., Cuming A., Kamisugi Y., Angelis K. J. and Fajkus J. (2019). Roles of RAD51 and RTEL1 in telomere and rDNA stability in Physcomitrella patens. Plant J. doi: 10.1111/tpj.14304 The author contributed to this publication by performing the sequence analysis of the rDNA intergenic spacer in Physcomitrella patens. The analysis included the prediction of potential G-quadruplex sites and the prediction of rRNA transcription start site. Table of contents 1. Introduction ................................................................................................................................... 11 2. Chromatin ...................................................................................................................................... 13 2.1. Nucleosomes ......................................................................................................................... 13 2.2. Chromatin interactions.......................................................................................................... 14 2.3. Chromatin states ................................................................................................................... 15 2.4. Chromatin maintenance during the genome replication ...................................................... 16 2.5. Chromatin Assembly Factor 1 ............................................................................................... 18 2.6. Chromatin Assembly Factor 1 in Arabidopsis thaliana ......................................................... 20 2.7. Nucleolus ............................................................................................................................... 22 3. Ribosomal DNA .............................................................................................................................. 25 3.1. Ribosomal DNA loci ............................................................................................................... 25 3.2. 5S rDNA ................................................................................................................................. 27 3.3. 45S rDNA ............................................................................................................................... 28 3.4. 45S rDNA intergenic spacer ................................................................................................... 29 3.5. 45S rDNA intergenic spacer in Arabidopsis thaliana ............................................................. 30 3.6. Regulation of rRNA gene variants in Arabidopsis thaliana ................................................... 31 4. Ribosomal DNA instability in Physcomitrella patens ..................................................................... 35 4.1. Physcomitrella patens ........................................................................................................... 35 4.2. Ribosomal DNA instability in pprad51 and pprtel1 mutants ................................................. 35 5. G-quadruplexes ............................................................................................................................. 37 5.1. Prediction of potential G-quadruplexes ...............................................................................
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