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Interactions of G-quadruplexes with chromophores
ID Peterková, Kateřina (Author), ID Plavec, Janez (Mentor) More about this mentor... This link opens in a new window

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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.

Language:English
Keywords:-
Work type:Doctoral dissertation
Typology:2.08 - Doctoral Dissertation
Organization:FKKT - Faculty of Chemistry and Chemical Technology
Year:2023
PID:20.500.12556/RUL-146119 This link opens in a new window
COBISS.SI-ID:163404035 This link opens in a new window
Publication date in RUL:19.05.2023
Views:584
Downloads:99
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Secondary language

Language:Slovenian
Title:Interakcije G-kvadrupleksov s kromoforji
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.

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