doctoral dissertation
Kateřina Peterková (Author), Janez Plavec (Mentor), Radek Marek (Mentor), Jurij Lah (Thesis defence commission member), Miha Pavšič (Thesis defence commission member), Lukáš Žídek (Thesis defence commission member), Lukáš Trantírek (Thesis defence commission member)

Abstract

The ability of nucleic acids to fold into higher-order non-canonical structures has been postulated and later proven to play an indispensable role in many biological and biomedical processes, such as control of promoter activity and genome instability. G-quadruplexes represent a family of structures adopted by both DNA and RNA sequences rich in guanine. Due to their overrepresentation in regions implicated in essential cellular processes, mutations in G-quadruplex forming sequences often result in development of various diseases, including cancer. Several approaches with the potential to elucidate therapeutical response by manipulating G-quadruplex structures found in promoter and telomeric regions have been suggested. This dissertation thesis summarizes results from two projects focused on covalent and non-covalent interactions of biologically relevant G-quadruplexes with small molecules. First, we aimed to design stable G-quadruplex decoys by incorporation of pyrene-conjugated nucleotide in the sequence of the c-kit2 G-quadruplex located in the KIT proto-oncogene. If successful, G-quadruplex decoys are expected to sequester essential transcription factors and thus suppress KIT expression and consequently cell growth and cancer progression. We provide structural details of three thermally stable G-quadruplex decoys, which vary in accessibility of outer G-quartets. Our results serve as guideline for design of G-quadruplex decoys derived from other biologically relevant G-rich sequences. Secondly, we studied binding of a novel osmium polypyridyl probe to the structure of G-quadruplexes derived from promoter of the cMYC proto-oncogene and from human telomere. Our NMR studies revealed that the enantioselectivity of binding is greatly dependent on the G-quadruplex topology. We show the importance of combining structural and photophysical studies to characterize the impact of binding on G-quadruplex structure and on the luminescence response.

Keywords

G-kavdrupleks;KIT;cMCY;hTel;NMR spektroskopija;kromofor;osmij;DNA-ligand interakcije;doktorske disertacije;nucleic acids;G-quadruplex;cMYC;NMR spectroscopy;chromophore;osmium;DNA-ligand interaction;

Data

Language: English
Year of publishing:
Typology: 2.08 - Doctoral Dissertation
Organization: UL FKKT - Faculty of Chemistry and Chemical Technology
Publisher: [K. Peterková]
UDC: 577.21
COBISS: 163404035 Link will open in a new window
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Downloads: 42
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Other data

Secondary title: Interakcije G-kvadrupleksov s kromoforji
Secondary abstract: Nukleinske kisline se lahko zvijejo v nekanonične strukture višjega reda za katere je bilo dokazano, da igrajo pomembno vlogo pri številnih bioloških in biomedicinskih procesih kot so npr. regulacija aktivnosti promotorjev in nestabilnost genoma s povečano pojavnostjo mutacij. G-kvadrupleksi predstavljajo družino struktur, ki jih zavzamejo zaporedja DNA in RNA, bogata z gvaninom. Zaradi visoke zastopanosti z gvaninom bogatih regij v predelih genoma, ki so vpleteni v ključne celične procese, mutacije v zaporedjih, ki tvorijo G-kvadruplekse, pogosto vodijo k razvoju različnih bolezni, vključno z rakom. Predlaganih je bilo več pristopov kjer bi do terapevtskega odziva prišli z manipulacijo G-kvadrupleksnih struktur, ki jih najdemo v promotorskih in telomernih regijah genoma. Ta disertacija povzema rezultate dveh projektov, osredotočenih na kovalentne in nekovalentne interakcije biološko pomembnih G-kvadrupleksov z malimi molekulami. V prvem delu smo želeli pripraviti stabilne G-kvadrupleksne vabe z vključitvijo nukleotida, konjugiranega s pirenom. Naša osnova je bilo zaporedje G-kvadrupleksa c-kit2, ki se nahaja v protoonkogenu KIT. S pirenom konjugirane G-kvadrupleksne vabe bi vezale ključne transkripcijske faktorje in tako zavrle izražanje KIT ter posledično celično rast in napredovanje raka. Raziskali smo strukturne podrobnosti treh termično stabilnih G-kvadrupleksnih vab z različnim pozicioniranjem pirenskih skupin ob zunanjih G-kvartetih. Naši rezultati bodo služili kot vodilo za načrtovanje G-kvadrupleksnih vab, pridobljenih iz drugih biološko pomembnih zaporedij, bogatih z gvaninom. V nadaljevanju smo preučevali vezavo nove osmijeve polipiridilne sonde na strukturo G-kvadrupleksov, pridobljenih iz promotorja protoonkogena cMYC in iz človeških telomerov. Naše študije so pokazale, da je enantioselektivnost vezave močno odvisna od topologije samega G-kvadrupleksa. Kombinacija strukturnih in fotofizičnih študij se je izkazala za idealno pri karakterizacije vezave sond na G-kvadruplekse in posledično spremembe v luminiscenci.
Secondary keywords: Nukleinske kisline;Univerzitetna in visokošolska dela;
Type (COBISS): Doctoral dissertation
Study programme: 1000381
Embargo end date (OpenAIRE): 1970-01-01
Thesis comment: Univ. of Ljubljana, Fac. of Chemistry and Chemical Technology
Pages: XVII, 211 f.
ID: 18957958