Regulation of the ups pili system involved in dna damage response in sulfolobus

Regulation of the Ups pili system involved in DNA damage response in Sulfolobus Inaugural-Dissertation zur Erlangung des Doktortorwürde der Naturwissenschaften (Dr rer nat.) am Fachbereich Biologie der Albert-Ludwigs-Universität Freiburg im Breisgau Thuong Ngoc Le geboren am 19.08.1988 in Thai Nguyen, Vietnam Regulation of the Ups pili system involved in DNA damage response in Sulfolobus Inaugural-Dissertation zur Erlangung des Doktortorwürde der Naturwissenschaften (Dr rer nat.) am Fachbereich Biologie der Albert-Ludwigs-Universität Freiburg im Breisgau Thuong Ngoc Le geboren am 19.08.1988 in Thai Nguyen, Vietnam The light microscopy picture on the cover shows S acidocaldarius cells forming aggregates due to UV irradiation The picture was taken by Thuong Ngoc Le Die vorliegende Arbeit wurde von Febuary 2014 bis August 2014 am Max-Planck Institut für terrestrische Mikrobiologie in Marburg und von September 2014 bis Marz 2018 an der Albert-Ludwigs-Universität Freiburg in der Arbeitsgruppe von Frau Prof Dr Sonja-Verena Albers durchgeführt Dekanin der Fakultät für Biologie: Prof Dr Bettina Warscheid Promotionsvorsitzender: Prof Dr Andreas Hiltbrunner Betreuer der Arbeit: Referent: Prof Dr Sonja-Verena Albers Koreferent: Drittprüfer: Datum der mündlichen Prüfung: The results that I have achieved during my Ph.D., which are described in this thesis, are published or to be published in the following peer review articles: Thuong Ngoc Le, Alexander Wagner and Sonja-Verena Albers A conserved hexanucleotide motif is important in UV-inducible promoters in Sulfolobus acidocaldarius Microbiology 2017;163: 778-788 Frank Schult1, Thuong Ngoc Le2, Andreas Albersmeier3, Bernadette Rauch1, Jörn Kalinowski3, Sonja-Verena Albers2 and Bettina Siebers1# Effect of UV irradiation on Sulfolobus acidocaldarius and involvement of the general transcription factor TFB3 in early UV response Molecular Microbiology (in submission) Table of contents INTRODUCTION 1.1 Transcription in archaea: a mosaic of eukaryotic and bacterial features 1.1.1 Basal transcriptional machinery in archaea 1.1.2 Regulation of transcription in archaea 1.1.2.1 Regulation of transcriptional initiation by general transcription factors 1.1.2.2 Regulatory motifs in archaeal promoters 1.1.2.3 Gene-specific transcriptional regulators: repressors, activators 1.1.2.4 The role of chromatin binding proteins in transcription regulation 1.1.2.5 The regulatory role of non-coding RNAs (ncRNAs) in gene expression 1.2 The DNA damage response in hyper-thermophilic archaea 1.2.1 The DNA damage response (DDR) 1.2.1.1 UV - induced DNA damages 1.2.1.2 DNA repair mechanisms 10 1.2.2 The UV response in Sulfolobus is part of the DNA damage response 11 1.2.2.1 The hyper-thermophilic Sulfolobus 11 1.2.2.2 The Ups system in Sulfolobus 12 1.2.2.3 The Ced system 14 1.2.3 Regulation of the Ups and Ced system in Sulfolobus 14 1.2.3.1 Transcription factor B3 (TFB3) 14 1.2.3.2 Other players might be involved in regulation of the UV response in Sulfolobus 15 1.3 MoxR-like protein family 16 1.3.1 MoxR proteins’ characteristics and cellular functions 16 1.3.2 The moxR-vWA3 operon in Sulfolobus acidocaldarius 18 1.4 Scope of the thesis 19 RESULTS 20 Research article 21 A conserved hexanucleotide motif is important in UV-inducible promoters in Sulfolobus acidocaldarius 21 Research article 37 Effect of UV irradiation on Sulfolobus acidocaldarius and involvement of the general transcription factor TFB3 in early UV response 37 Research article 72 Characterization of a MoxR AAA+ ATPase in Sulfolobus acidocaldarius 72 DISCUSSION 97 3.1 The role of the transcription factor TFB3 in the transcriptional regulatory network in response to UV-induced damage DNA in Sulfolobus 99 3.2 Transcriptional regulators and chromatin-binding proteins: their interplay and evolutionary relationship 103 Thesis summary 108 Zusammenfassung 109 References 110 Acknowledgment 116 Introduction INTRODUCTION Introduction 1.1 Transcription in archaea: a mosaic of eukaryotic and bacterial features 1.1.1 Basal transcriptional machinery in archaea Forty years ago, based on the 16s rRNA gene sequences, archaea were recognized as the third domain of life next to bacteria and eukaryotes (Woese et al., 1990; Woese & Fox, 1977) Since that milestone of evolution biology, a great number of studies have unveiled more unique characteristics of archaea that make them a separated domain (White, 2006; Cavicchioli, 2010; Werner & Grohmann, 2011; Albers & Meyer, 2011; Lindås & Bernander, 2013; Karr et al., 2017) Nowadays, it is well established that archaea possess a transcription apparatus resembling a simplified version of the eukaryotic RNA polymerase (RNAP) II system (Soppa 1999; Geiduschek & Ouhammouch 2005; Grohmann & Werner 2011; Orell et al 2013; Karr 2014; Gindner et al 2014; Kessler et al 2015) Studies on archaeal RNAP from Sulfolobus acidocaldarius delivered the first hint that archaea might initiate transcription in a eukaryotic manner (Zillig et al., 1979) Archaeal RNAP is a protein complex composed of 13 subunits of which each individual subunit is highly conserved and homologous to that of eukaryotic RNAP II (Langer et al., 1995; Grohmann et al., 2009) Subsequently, the canonical core promoter of archaea was shown to harbor a TATA box, an AT-rich region located around -26 to -30 bp upstream of the transcription start site (TSS) Directly upstream of the TATA box is a purine-rich segment named transcription factor B recognition element (BRE) (Soppa 1999; Qureshi et al 1997) There are other less defined DNA elements in archaeal promoters, such as the initiator element (INR), and the promoter proximal element (PPE) (Peng et al., 2009a; Soppa, 1999b) However, the presence of the INR and PPE varies among different groups of archaea For example, the INR positioned within the initially transcribed region is hardly detectable in haloarchaeal promoters, but very pronounced in methanogens and Sulfolobales (Soppa, 1999b) The PPE located between the TATA box and the TSS has been found primarily in Sulfolobus promoters (Peng et al., 2009a, 2011; Wurtzel et al., 2010) Neither RNAPII nor RNAP can be recruited to promoters without the aid of transcription factors (Blombach & Grohmann, 2017; Langer et al., 1995; Soppa, 1999a) So far, three types of transcription factors involving initiation of archaeal transcription have been well studied They are TATA-binding proteins (TBPs), transcription factor B (TFBs), and Discussion contains the hexanucleotide motif (research article 1) Moreover, the hexanucleotide motif is wide spread in promoters of tfb3 and genes whose transcriptions are dependent on TFB3 suggests another hierarchy level of the transcriptional regulatory network of UV response in Sulfolobus Clearly, the regulation of the UV transcription response in Sulfolobus is highly diverse with the participation of presumably multiple regulators and promoter elements A similar scenario has been seen in the regulation of the archaella expression The archaellum regulatory network (Arn) contains multiple repressors ArnA, ArnB, activators ArnR, ArnR1, the kinases ArnC, ArnD, phosphorylase PP2A, ArnS (Haurat et al., 2017; Lassak et al., 2013; Reimann et al., 2012, 2013) Besides that, the biofilm regulator AbfR1 also has a positive effect on the expression of the archaella (Li et al., 2017; Orell et al., 2013) It is known in bacteria that transcription factors evolve faster than their target genes suggesting that transcriptional regulatory networks are highly dynamic and flexible (van Hijum et al., 2009) The complex of the transcriptional regulatory network in Sulfolobus might be rooted from the fact that Crenarchaea possess only the one-component system (OCs) (Ashby 2006; Coulson et al 2007) Transcription factors in the OCs often contain both the DNA-binding domain (HTH domain) and the sensing domain However, a great number of archaeal transcription factors are single-domain proteins solely composed of a DNA-binding domain (Aravind and Koonin 1999; Perez Rueda and Janga 2010) Consequently, the average size of archaeal TFs is smaller than that of bacterial TFs (a median size of 179 versus 236 amino acids, respectively) (Pérez-Rueda and Janga 2010) In archaea, the number of TFs is in line with the genome size while the diversity in TF families is not (Pérez-Ruedaand Janga 2010; Martínez-Núnez et al 2013) Since gene duplications resulted in lineage-specific expansions of TF paralogues within specific families (Martínez-Nunez et al 2013; Plaisier et al 2014) Moreover, archaea seem to have lower proportions of genes that encode TFs as compared to bacteria (Minezaki et al 2005; Pérez-Rueda and Janga 2010; Martínez-Nunez et al 2013) In comparison to bacteria, it was fascinating that archaea are able to regulate the similar size of genomes with a more limited repertoire of TFs which are smaller and less diverse than the bacterial counterparts Might it be the limitation in number and diversity of archaeal TFs result in the quick evolution of TFs to fulfill the requirement of environmental adaptation? This is also my second discussion part where I focus on the hypotheses that archaeal 102 Discussion transcriptional regulators might be evolved from chromatin-binding proteins to serve new functions, however, some still keep their precursor architectural role 3.2 Transcriptional regulators and chromatin-binding proteins: their interplay and evolutionary relationship For prokaryotes, the task of fitting the entire genomic DNA into the confined space of a cell is essential for survival (Campbell, 1993) If a bacterium is unable to organize and compact its genomic DNA, as well as replicate and express it in a reasonably reliable way, it will not be viable Whereas, transcription regulation that is also very important but may not be essential for survival (Visweswariah and Busby 2015) Therefore, it has been postulated that early in evolution only chromatin proteins existed and solely functioned in genome compaction (Visweswariah and Busby 2015) Later in evolution, some of the chromatin proteins also took on a transcription regulatory function upon binding in the neighborhood of TSS, thereby conferring a fitness advantage to the organism (Figure 1) Thus, the existing TFs have thus evolved from non-specifically binding chromatin proteins and while some of these have become dedicated TFs, others still combine both functions (Visweswariah and Busby 2015) For instance, the cyclic AMP receptor protein (CRP) in bacteria, as a classic transcription factor, was extensively studied and often referred to as a paradigm (Beatty et al., 2003; de Crombrugghe et al., 1984; Shinkai et al., 2007) However, recent studies have indicated CRP is more likely a nucleoid-associated protein involved in the organization of the bacterial chromosome, and maybe, just at a subset of its targets, it has been recruited to mediate the activation of neighboring genes (Kahramanoglou et al., 2014) In archaea, it is also difficult to draw a distinct line between ‘’true’’ transcription regulators and “true” chromatin proteins (Karr et al., 2017) With the use of genome-wide ChIP studies, it turned out that archaeal TFs bind to more target sites than the anticipations based on their physiological role and/or regulatory target genes These additional sites are located at a significant distance from transcription start sites, and are often intragenic (Efremov et al., 2015; Nguyen-Duc et al., 2013; Song et al., 2013) Archaeal transcription regulators with their bacterial nature could be also evolved in a similar way as the bacterial counterparts 103 Discussion Figure Evolution of nucleoid-associated proteins into transcription factors (A) A segment of a bacterial chromosome containing four promoters that are being served by RNA polymerase molecules, denoted by beige blobs that create transcripts indicated by horizontal arrows Nucleoid-associated proteins, denoted by pink and green blobs bind at diverse sites and we envisage them down-regulating promoter activity in a non-targeted way (B) Some of the nucleoid-associated proteins evolve specifically to efficiently repress three of the promoters This involves dimerization, illustrated by light blue intertwined blobs, with a concomitant increase in DNA-binding affinity and specificity (C) One of the repressors acquires a ligandresponsive module that permits the host to modulate transcription at the target promoter in response to a signal (D) Certain repressors become activators by the acquisition of activating regions that recruit RNA polymerase to the cognate target Figure and legend were exported from (Visweswariah & Busby, 2015) Each archaeal genome harbors at least two different types of chromatin proteins with distinct architectural properties (Peeters et al., 2015) The nucleoid in Euryarchaea is mainly organized by histone-like proteins that bend or wrap DNA, as well as by Alba that binds to DNA as a homodimer or a heterodimer (Reeve 2003; Goyal et al 2016) Crenarchaea, on the other hand, organize their nucleoid by using proteins that bend DNA such as Cren7 and Sul7 in Sulfolobus spp as well as by Alba (Reeve 2003; Ammar et al 2012; Goyal et al 2016) Besides functioning as genomic architectural proteins, these chromatin proteins have been found to act as gene-specific regulators in some circumstances (Goyal et al., 2016; Karr et al., 2017; Peeters et al., 2015) Especially, the Alba family proteins that are widely distributed in archaea were demonstrated to regulate gene expression (Goyal et al., 2016) For instance, in Methanococcus maripaludis, the Alba protein named Mma10b, is expressed at lower levels than its orthologue in 104 Discussion Sulfolobus shibatae and binds to DNA in a sequence-specific manner (Liu et al., 2009), which both are typical characters of a transcription factor Moreover, deletion of Mma10b homolog in Methanococcus voltae has been shown to result in up-regulation of several genes involved in carbon dioxide assimilation, including the gene encoding pyruvate ferredoxin oxidoreductase, which suggests that Mma10b has a specific gene regulatory role in autotrophic growth (Heinicke et al., 2004) Furthermore, studies of the protein Alba1 in Sulfolobus spp revealed that Alba1 is acetylated by protein acetyltransferase (Pat) at Lys16 on the DNA-binding surface and deacetylated by the silent information regulator (Sir2) (Bell, 2002; Marsh et al., 2005) In an in vitro transcription system, it was shown that the recombinant (non-acetylated) Alba1 repressed transcription, whereas native (acetylated) Alba1 purified from S solfataricus did not (Bell, 2002) Thus, the acetylation state of Alba1 seems potentially regulate transcription in vivo Nevertheless, the Lys16 residue of Alba1 is not conserved in all archaeal species, which suggests that this mode of regulation is not universal (Liu et al., 2009) Figure Putative transcription regulatory mechanisms of chromatin proteins in archaea a ) Histone proteins compete for DNA binding with the transcription initiation factors TATA-binding protein (TBP) and transcription factor B (TFB) to their respective promoter elements, the TATA box and Brecognition element (BRE) Depending on many factors (for example, expression levels of chromatin proteins and their DNA- binding affinity), either histones or the initiation factors bind to the DNA, and transcription initiation is repressed or permitted, respectively B) During transcription elongation, DNAbound histones reduce RNA polymerase (RNAP) elongation rates, but elongation is not completely abrogated c) Acetylation of the Lys16 residue (K16ac) of Alba1 reduces its DNA-binding affinity It has been suggested that this post-translational modification has a role in global gene regulation by permitting access of transcription factors to the promoter site Figure and legend were exported from (Peeter et al 2015) Vice versa, some transcriptional regulators also work as chromatin proteins such as the TrmBL2 regulator in Euryarchaea The TrmB family of TFs has been well studied (Gindner 105 Discussion et al 2014; Kim et al 2016) and are defined as sugar-responsive specific transcriptional regulators (Lee et al 2003; Gindner et al 2014) However, the related TrmBL2 appears to have a function in chromatin organization (Maruyama et al 2011) It is due to the observation that TrmBL2 is constitutively expressed in Thermococcales (Lee et al 2003) Moreover, TrmBL2 binding results in the formation of thick filamentous nucleoprotein structures which are assumed to play a role in chromatin organization by antagonizing the packaging of DNA and competing with histones for binding (Maruyama et al 2011; Efremov et al 2015) Nevertheless, TrmBL2 also acts as a global TF by repressing about 6.5% of all genes in the genome of P furiosus (Maruyama et al 2011) In addition, the Lrs14-like family proteins in Sulfolobus spp that was initially defined classical TFs (Napoli et al 1999; Bell and Jackson 2000; Fiorentino et al 2003) also appear to function as chromatin-organizing proteins For instance, the biofilm regulator AbfR1 in Sulfolobus was found to bind to a variety of DNA templates in a non-sequence specific manner and induce strong DNA topological changes (Orell et al 2013, Li et al 2017) Furthermore, protein Smj12, a homolog of Lrs14, in S solfataricus induces positive DNA supercoiling and protects the DNA from thermodenaturation, which indicates its putative role in DNA-structuring (Napoli et al 2001) In addition, different Lrs14-like proteins have been retrieved together with chromatin proteins Alba and Sso7d in pulldown assays with a variety of bait DNA fragments (Napoli et al 2001; Fiorentino et al 2003; Kessler et al 2006; Abella et al 2007) These mentioned examples are good indications of proteins that evolved to become transcription factors but still keep their chromatin architectural functions Back to the regulation of genes response to UV stress in Sulfolobus, it is possible that TFB3 acts on its regulatory function cooperatively with chromatin-associated proteins such as Alba1 I suspect that in normal growth condition, genes that are responsible for UV response are blocked or expressed at low level due to the occupation of Alba1 proteins (presumed at non-acetylated state which has high affinity to DNA) When the blockage of Alba1 is loosened or lifted, these UV inducible genes can be expressed at high level Indeed, it was shown that after UV-inducible DNA damage in Sulfolobus, Alba1 proteins are acetylated by a protein acetyltransferase (Pat), which decrease their affinity to DNA Therefore, the acetylation of Alba proteins after UV stress makes the promoter regions of UV-inducible genes become more accessible At this point, the basal transcription factors 106 Discussion (TBP, TFB) to some extent could access to the promoter and initiate transcription of genes that are UV-regulated but independent from TFB3 However, the transcription of other genes such as ones are transcribed in TTFB3-dependent manner is only boosted to a high level with the help of TFB3 protein In addition, transcriptional regulators such as the SaLrp also are involved in activating transcription of UV-induced genes such as the upsA Following I describe my proposal of the putative model of transcription regulation of UVinduced genes (the ups genes) in response to UV stress in Sulfolobus (Figure 3) Figure 3: Model of regulation of the ups gene cluster in response to UV irradiation in Sulfolobus To address the role of Alba1 or other chromatin-binding proteins in transcription of UV regulated genes I suggested further experiments as followed Indeed, I had performed the pull-down assay used biotinylated promoters of UV-inducible genes (such as upsX) in both non-UV and UV treatment conditions The idea of this assay is to identify or exclude the putative repressor that could theoretically fulfill the function of Alba1 in inhibiting the transcription under non-UV condition So far, I could not identify any regulators that directly interact/bind to the biotinylated promoter Alternatively, in vitro transcription could be applied to investigate the role of Alba1 or chromatin-associated proteins in transcription of the UV-induced genes The data obtained from these experiments would provide a novel mechanism of gene activation in response to DNA damage in Sulfolobus 107 References Thesis summary Maintenance of the genome integrity is a vital task of all living organisms Studies of DNA damage in bacteria and eukaryotes have revealed interesting sophisticated pathways known as the DNA damage response Sulfolobus spp known to thrive in harsh habitats is an interesting model to discover the way that archaea handle environmental stress caused DNA damages Previous microarray studies in Sulfolobus revealed a transcriptional response to DNA damage caused by UV irradiation including the up-regulation of the ups, the ced genes and especially the transcription factor TFB3 Previous studies have revealed the roles of the Ups pili and the Ced system in DNA transfer after UV irradiation as well as the function of TFB3 in activating transcription in vitro Based on these prior findings, I have pursued the work to gain insights into mechanisms that regulate the transcription of UV-regulated genes with a primary focus on the ups and the ced genes The results of my work have been described in research articles in chapter In research article 1, I described a conserved motif in promoters of the ups genes, which is important for their transcription This motif is also found in a total number of more than 200 promoters of other genes including ones that are highly UV-induced promoters such as tfb3, saci_0667, cdc 6-2, saci_0951 and saci_1225, slight UV-induced genes, and genes are down-regulated after UV stress It has been the first DNA motif that involves transcription of UV-regulated genes in archaea has been studied Following the findings of the UV-induced motif, in research article 2, I described the function of TFB3 in regulation of genes that are highly up-regulated by UV, including the ups and ced genes The deep sequencing data revealed the early induction of TFB3 after UV irradiation then followed by the up-regulation of genes whose transcription depends on TFB3 The disruption of tfb3 in Sulfolobus cells impairs the Ups pilus formation leading to no cell aggregates after UV treatment Moreover, in this article, I indicated that TFB3 could work cooperatively with the Sa-Lrp regulator in regulation of UV-induced genes such as upsA Finally, in the article 3, I presented the extended data of the characterization of MoxR protein from S acidocaldarius, a protein that was initially found as a putative interaction partner of UpsX Further, I discussed some interesting potential speculation of the transcriptional regulatory network of UV response in Sulfolobus and suggested some further experiments for future studies In the end, I proposed a putative model of the transcription regulation of the exemplified ups cluster in response to UV light 108 References Zusammenfassung Der Erhalt der DNS, des Erbgutes eines jeden Organismus, ist eine essenzielle Aufgabe um das Überleben einer Spezies gewährleisten zu können Eine Vielzahl an Studien hat ergeben, dass Bakterien und Eukaryoten verschiedene Mechanismen besitzen, um DNS-Schäden zu reparieren Sulfolobus spp gehören zu der Domäne der Archäen und leben unter, aus menschlicher Sicht, widrigen Umständen- d.h sie wachsen bei 75°C und sehr sauren pHWerten Da diese Bedingungen als sehr schädlich für die Genomstabilität gelten, ist Sulfolobus ein geeigneter Modelorganismus, um DNS-Reparaturmechanismen in Archäen zu studieren Vorangegangene Microarray-Studien haben ergeben, dass Sulfolobus spp eine transkritpionelle Antwort auf UV-Licht induzierte DNS-Schäden besitzen, welche die Hochregulation sowohl der ups- und ced-Gene, als auch des tfb3-Gens beinhaltet Ups-pili und das Ced-system sind essenziell für den spezies-spezifischen Austausch der DNS bei Sulfolobus spp nach erfolgtem DNS-Stress TFB3 ist ein Transkriptionsfaktor, dessen Funktion als transkriptioneller Aktivator in vitro gezeigt wurde Basierend auf diesen Ergebnissen habe ich es mir zum Ziel gesetzt, ein detailliertes Verständnis über die Regulation UV-Licht induzierbarer Gene, mit Fokus auf die upsund ced-Gene, zu gewinnen Die Ergebnisse meiner Arbeit habe ich in drei Forschungsartikeln, zu finden in Kapitel 2, beschrieben In Forschungsartikel beschreibe ich ein konserviertes DNS-Motiv in den Promotoren der upsGene, welches essenziell für deren Transkription ist Das hier identifizierte DNS-Motiv ist in mehr als 200 Promoterregionen von Genen zu finden, die nach DNS-Stress hoch reguliert (tfb3, saci_0667, cdc6-2, saci951 und saci1225) oder herunter reguliert sind Dieses DNS-Motivs ist die erste Beschreibung einer archaeallen DNS-Sequenz, welche UV-regulierte Gene kontrolliert In Forschungsartikel beschreibe ich die Funktion von TFB3 in der Aktivierung UV-induzierbarer Gene wie die ups- und ced-Gene Deep-Sequencing-Daten zeigen, dass TFB3 früh nach erfolgtem UV-Stress induziert ist Darauffolgend werden weiter Gene in Abhängigkeit von TFB3 aktiviert Eine tfb3-Insertionsmutante ist nicht mehr in der Lage, nach erfolgtem UV-Stress physischen Kontakt aufzunehmen und kann deshalb wahrscheinlich auch keine DNS mehr austauschen In diesem Artikel diskutiere ich auch die Rolle des Regulators Sa-Lrp, der zusammen mit TFB3 UV-induzierbare Gene wie upsA zu regulieren scheint Forschungsartikel beschreibt schliesslich weitere Daten zu MoxR, welches als möglicher Interaktionspartner von UpsX gefunden wurde Weiterhin diskutiere ich das transkriptionelle Netzwerk von Sulfolobus spp nach erfolgtem DNS-Stress, unterlege diese Diskussion mit einem Modell und schlage fortführende Experimente vor, welche ein besseres Verständnis über das Überleben dieser Archäen liefern können 109 References References Ajon, M., Fröls, S., van 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I still remember almost years ago the first day I came to Sonja’s lab with a taxi because I was lost in the city center of Marburg and did not know how to catch the bus During those years, I have learned how to work with Sulfolobus, moved to a new city, met new friends, said goodbye to old friends, and now I am writing the acknowledgment of my thesis! At this point, no matter how upset I was sometimes with experiments, with foods, and with some down moments, I am grateful for all things that have occurred, all people that I have chances to meet and work with First of all, I would like to thank Sonja for giving me the opportunity to work in your wonderful lab and for all the supports that you generously offer me! You motivate and inspire us by your enthusiasm and passion for science and for Sulfolobus From you, I have learnt how to work as a professional scientist, be responsible, straightforward and cooperative with colleagues I also would like to thank Chris for your inspiration and critical suggestions whenever I need an advice for my experiments You and Sonja are both great scientists and great leaders of our team! Especially, I would like to give a big thank to Alex and Marleen for all your help, encourages and scientific discussions Alex, I really enjoyed the time that we worked together Your motivation, creative thinking, and your scientific knowledge are valuable things that make me feel very lucky to have a chance to work with you In addition, my thesis cannot be finished without your critical proofreading and suggestions Marleen, you were the one who taught me the very beginning things about Sulfolobus, you were also the one who came and checked for my apartment when I was still in Vietnam Specially, your passion in science, your creativity in working as well as your fairness in dealing with issues in the lab are impressed me in many ways By the way, I also like your fashion style very much!  Further, I would like to thank Florencia for all your suggestions for my experiments, your patience in listening to my presentation rehearsals, your gifted talent in locating missing things, and of course your kindness and great humor! Paushali, Rashmi, Xing, ZhangQin, and Fernando, thank you guys for all the fun that we had in the lab It was Paushali‘s laughing, the time we spent together in Corsica, the dinners we had together that makes my life more lively and cheerful A special thank to my friend Lingling for your kindness, your hospitality, and lovely nature How easy it was to tell you anything in my head and got the words from your heart I also would like to thank Astrid for always being helpful whenever I came and ask for Thanks to all the people in the Badminton group, Jan, Patrick, Nuno, Nienke, Alex, Lena for the fun of playing and all other people whose names I could not mention here All of you are great and supportive colleagues, also cool and funny friends to hang out Finally, I am thankful for the love and support of my family, my parents and my brother My big hug to Lan, Nga, Mai Anh who are my friends and my sisters Moreover, Nu “beo”, thank you for being with me, patiently help me get through my tough time Without you, I would not have been strong enough to confront and get over it You have brought me a friend, a mommy and a family Für Mama und Chef, ich danke euch für alles! 116 ... 1.1.2.4 The role of chromatin binding proteins in transcription regulation 1.1.2.5 The regulatory role of non-coding RNAs (ncRNAs) in gene expression 1.2 The DNA damage response in hyper-thermophilic... The DNA damage response (DDR) 1.2.1.1 UV - induced DNA damages 1.2.1.2 DNA repair mechanisms 10 1.2.2 The UV response in Sulfolobus is part of the DNA damage response. .. 1.2.2.1 The hyper-thermophilic Sulfolobus 11 1.2.2.2 The Ups system in Sulfolobus 12 1.2.2.3 The Ced system 14 1.2.3 Regulation of the Ups and Ced system in Sulfolobus