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Artykuły w czasopismach na temat "DNA repair, helicase, G-quadruplex"
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Sun, Zhi-Yin, Xiao-Na Wang, Sui-Qi Cheng, Xiao-Xuan Su i Tian-Miao Ou. "Developing Novel G-Quadruplex Ligands: from Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction". Molecules 24, nr 3 (22.01.2019): 396. http://dx.doi.org/10.3390/molecules24030396.
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G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has become a novel promising anti-tumor strategy. Different kinds of small molecules targeting the G-quadruplexes have been designed, synthesized, and identified as potential anti-tumor agents, including molecules directly bind to the G-quadruplex and molecules interfering with the binding between the G-quadruplex structures and related binding proteins. This review will explore the feasibility of G-quadruplex ligands acting as anti-tumor drugs, from basis to application. Meanwhile, since helicase is the most well-defined G-quadruplex-related protein, the most extensive research on the relationship between helicase and G-quadruplexes, and its meaning in drug design, is emphasized.
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Wu, Yuliang, Kazuo Shin-ya i Robert M. Brosh. "FANCJ Helicase Defective in Fanconia Anemia and Breast Cancer Unwinds G-Quadruplex DNA To Defend Genomic Stability". Molecular and Cellular Biology 28, nr 12 (21.04.2008): 4116–28. http://dx.doi.org/10.1128/mcb.02210-07.
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ABSTRACT FANCJ mutations are associated with breast cancer and genetically linked to the bone marrow disease Fanconi anemia (FA). The genomic instability of FA-J mutant cells suggests that FANCJ helicase functions in the replicational stress response. A putative helicase with sequence similarity to FANCJ in Caenorhabditis elegans (DOG-1) and mouse (RTEL) is required for poly(G) tract maintenance, suggesting its involvement in the resolution of alternate DNA structures that impede replication. Under physiological conditions, guanine-rich sequences spontaneously assemble into four-stranded structures (G quadruplexes [G4]) that influence genomic stability. FANCJ unwound G4 DNA substrates in an ATPase-dependent manner. FANCJ G4 unwinding is specific since another superfamily 2 helicase, RECQ1, failed to unwind all G4 substrates tested under conditions in which the helicase unwound duplex DNA. Replication protein A stimulated FANCJ G4 unwinding, whereas the mismatch repair complex MSH2/MSH6 inhibited this activity. FANCJ-depleted cells treated with the G4-interactive compound telomestatin displayed impaired proliferation and elevated levels of apoptosis and DNA damage compared to small interfering RNA control cells, suggesting that G4 DNA is a physiological substrate of FANCJ. Although the FA pathway has been classically described in terms of interstrand cross-link (ICL) repair, the cellular defects associated with FANCJ mutation extend beyond the reduced ability to repair ICLs and involve other types of DNA structural roadblocks to replication.
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Shukla, Kaustubh, Roshan Singh Thakur, Debayan Ganguli, Desirazu Narasimha Rao i Ganesh Nagaraju. "Escherichia coli and Neisseria gonorrhoeae UvrD helicase unwinds G4 DNA structures". Biochemical Journal 474, nr 21 (18.10.2017): 3579–97. http://dx.doi.org/10.1042/bcj20170587.
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G-quadruplex (G4) secondary structures have been implicated in various biological processes, including gene expression, DNA replication and telomere maintenance. However, unresolved G4 structures impede replication progression which can lead to the generation of DNA double-strand breaks and genome instability. Helicases have been shown to resolve G4 structures to facilitate faithful duplication of the genome. Escherichia coli UvrD (EcUvrD) helicase plays a crucial role in nucleotide excision repair, mismatch repair and in the regulation of homologous recombination. Here, we demonstrate a novel role of E. coli and Neisseria gonorrhoeae UvrD in resolving G4 tetraplexes. EcUvrD and N. gonorrhoeae UvrD were proficient in unwinding previously characterized tetramolecular G4 structures. Notably, EcUvrD was equally efficient in resolving tetramolecular and bimolecular G4 DNA that were derived from the potential G4-forming sequences from the genome of E. coli. Interestingly, in addition to resolving intermolecular G4 structures, EcUvrD was robust in unwinding intramolecular G4 structures. These data for the first time provide evidence for the role of UvrD in the resolution of G4 structures, which has implications for the in vivo role of UvrD helicase in G4 DNA resolution and genome maintenance.
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Bryan, Tracy M. "Mechanisms of DNA Replication and Repair: Insights from the Study of G-Quadruplexes". Molecules 24, nr 19 (22.09.2019): 3439. http://dx.doi.org/10.3390/molecules24193439.
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G-quadruplexes are four-stranded guanine-rich structures that have been demonstrated to occur across the genome in humans and other organisms. They provide regulatory functions during transcription, translation and immunoglobulin gene rearrangement, but there is also a large amount of evidence that they can present a potent barrier to the DNA replication machinery. This mini-review will summarize recent advances in understanding the many strategies nature has evolved to overcome G-quadruplex-mediated replication blockage, including removal of the structure by helicases or nucleases, or circumventing the deleterious effects on the genome through homologous recombination, alternative end-joining or synthesis re-priming. Paradoxically, G-quadruplexes have also recently been demonstrated to provide a positive role in stimulating the initiation of DNA replication. These recent studies have not only illuminated the many roles and consequences of G-quadruplexes, but have also provided fundamental insights into the general mechanisms of DNA replication and its links with genetic and epigenetic stability.
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Byrd, Alicia K., i Kevin D. Raney. "Structure and function of Pif1 helicase". Biochemical Society Transactions 45, nr 5 (12.09.2017): 1159–71. http://dx.doi.org/10.1042/bst20170096.
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Pif1 family helicases have multiple roles in the maintenance of nuclear and mitochondrial DNA in eukaryotes. Saccharomyces cerevisiae Pif1 is involved in replication through barriers to replication, such as G-quadruplexes and protein blocks, and reduces genetic instability at these sites. Another Pif1 family helicase in S. cerevisiae, Rrm3, assists in fork progression through replication fork barriers at the rDNA locus and tRNA genes. ScPif1 (Saccharomyces cerevisiae Pif1) also negatively regulates telomerase, facilitates Okazaki fragment processing, and acts with polymerase δ in break-induced repair. Recent crystal structures of bacterial Pif1 helicases and the helicase domain of human PIF1 combined with several biochemical and biological studies on the activities of Pif1 helicases have increased our understanding of the function of these proteins. This review article focuses on these structures and the mechanism(s) proposed for Pif1's various activities on DNA.
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Schwab, Rebekka A., Jadwiga Nieminuszczy, Kazuo Shin-ya i Wojciech Niedzwiedz. "FANCJ couples replication past natural fork barriers with maintenance of chromatin structure". Journal of Cell Biology 201, nr 1 (25.03.2013): 33–48. http://dx.doi.org/10.1083/jcb.201208009.
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Defective DNA repair causes Fanconi anemia (FA), a rare childhood cancer–predisposing syndrome. At least 15 genes are known to be mutated in FA; however, their role in DNA repair remains unclear. Here, we show that the FANCJ helicase promotes DNA replication in trans by counteracting fork stalling on replication barriers, such as G4 quadruplex structures. Accordingly, stabilization of G4 quadruplexes in ΔFANCJ cells restricts fork movements, uncouples leading- and lagging-strand synthesis and generates small single-stranded DNA gaps behind the fork. Unexpectedly, we also discovered that FANCJ suppresses heterochromatin spreading by coupling fork movement through replication barriers with maintenance of chromatin structure. We propose that FANCJ plays an essential role in counteracting chromatin compaction associated with unscheduled replication fork stalling and restart, and suppresses tumorigenesis, at least partially, in this replication-specific manner.
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Lowran, Kaitlin, Laura Campbell, Phillip Popp i Colin G. Wu. "Assembly of a G-Quadruplex Repair Complex by the FANCJ DNA Helicase and the REV1 Polymerase". Genes 11, nr 1 (19.12.2019): 5. http://dx.doi.org/10.3390/genes11010005.
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The FANCJ helicase unfolds G-quadruplexes (G4s) in human cells to support DNA replication. This action is coupled to the recruitment of REV1 polymerase to synthesize DNA across from a guanine template. The precise mechanisms of these reactions remain unclear. While FANCJ binds to G4s with an AKKQ motif, it is not known whether this site recognizes damaged G4 structures. FANCJ also has a PIP-like (PCNA Interacting Protein) region that may recruit REV1 to G4s either directly or through interactions mediated by PCNA protein. In this work, we measured the affinities of a FANCJ AKKQ peptide for G4s formed by (TTAGGG)4 and (GGGT)4 using fluorescence spectroscopy and biolayer interferometry (BLI). The effects of 8-oxoguanine (8oxoG) on these interactions were tested at different positions. BLI assays were then performed with a FANCJ PIP to examine its recruitment of REV1 and PCNA. FANCJ AKKQ bound tightly to a TTA loop and was sequestered away from the 8oxoG. Reducing the loop length between guanine tetrads increased the affinity of the peptide for 8oxoG4s. FANCJ PIP targeted both REV1 and PCNA but favored interactions with the REV1 polymerase. The impact of these results on the remodeling of damaged G4 DNA is discussed herein.
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Wu, Yuliang, Joshua A. Sommers, Avvaru N. Suhasini, Thomas Leonard, Julianna S. Deakyne, Alexander V. Mazin, Kazuo Shin-ya, Hiroyuki Kitao i Robert M. Brosh. "Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein-DNA complexes". Blood 116, nr 19 (11.11.2010): 3780–91. http://dx.doi.org/10.1182/blood-2009-11-256016.
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Abstract Fanconi anemia (FA) is a genetic disease characterized by congenital abnormalities, bone marrow failure, and susceptibility to leukemia and other cancers. FANCJ, one of 13 genes linked to FA, encodes a DNA helicase proposed to operate in homologous recombination repair and replicational stress response. The pathogenic FANCJ-A349P amino acid substitution resides immediately adjacent to a highly conserved cysteine of the iron-sulfur domain. Given the genetic linkage of the FANCJ-A349P allele to FA, we investigated the effect of this particular mutation on the biochemical and cellular functions of the FANCJ protein. Purified recombinant FANCJ-A349P protein had reduced iron and was defective in coupling adenosine triphosphate (ATP) hydrolysis and translocase activity to unwinding forked duplex or G-quadruplex DNA substrates or disrupting protein-DNA complexes. The FANCJ-A349P allele failed to rescue cisplatin or telomestatin sensitivity of a FA-J null cell line as detected by cell survival or γ-H2AX foci formation. Furthermore, expression of FANCJ-A349P in a wild-type background exerted a dominant-negative effect, indicating that the mutant protein interferes with normal DNA metabolism. The ability of FANCJ to use the energy from ATP hydrolysis to produce the force required to unwind DNA or destabilize protein bound to DNA is required for its role in DNA repair.
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Gaur, Paras, Fletcher E. Bain, Masayoshi Honda, Sophie L. Granger i Maria Spies. "Single-Molecule Analysis of the Improved Variants of the G-Quadruplex Recognition Protein G4P". International Journal of Molecular Sciences 24, nr 12 (17.06.2023): 10274. http://dx.doi.org/10.3390/ijms241210274.
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As many as 700,000 unique sequences in the human genome are predicted to fold into G-quadruplexes (G4s), non-canonical structures formed by Hoogsteen guanine–guanine pairing within G-rich nucleic acids. G4s play both physiological and pathological roles in many vital cellular processes including DNA replication, DNA repair and RNA transcription. Several reagents have been developed to visualize G4s in vitro and in cells. Recently, Zhen et al. synthesized a small protein G4P based on the G4 recognition motif from RHAU (DHX36) helicase (RHAU specific motif, RSM). G4P was reported to bind the G4 structures in cells and in vitro, and to display better selectivity toward G4s than the previously published BG4 antibody. To get insight into G4P- G4 interaction kinetics and selectivity, we purified G4P and its expanded variants, and analyzed their G4 binding using single-molecule total internal reflection fluorescence microscopy and mass photometry. We found that G4P binds to various G4s with affinities defined mostly by the association rate. Doubling the number of the RSM units in the G4P increases the protein’s affinity for telomeric G4s and its ability to interact with sequences folding into multiple G4s.
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Ononye, Onyekachi E., Christopher W. Sausen, Lata Balakrishnan i Matthew L. Bochman. "Lysine acetylation regulates the activity of nuclear Pif1". Journal of Biological Chemistry 295, nr 46 (2.09.2020): 15482–97. http://dx.doi.org/10.1074/jbc.ra120.015164.
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In Saccharomyces cerevisiae, the Pif1 helicase functions in both nuclear and mitochondrial DNA replication and repair processes, preferentially unwinding RNA:DNA hybrids and resolving G-quadruplex structures. We sought to determine how the various activities of Pif1 are regulated in vivo. Here, we report lysine acetylation of nuclear Pif1 and demonstrate that it influences both Pif1's cellular roles and core biochemical activities. Using Pif1 overexpression toxicity assays, we determined that the acetyltransferase NuA4 and deacetylase Rpd3 are primarily responsible for the dynamic acetylation of nuclear Pif1. MS analysis revealed that Pif1 was modified in several domains throughout the protein's sequence on the N terminus (Lys-118 and Lys-129), helicase domain (Lys-525, Lys-639, and Lys-725), and C terminus (Lys-800). Acetylation of Pif1 exacerbated its overexpression toxicity phenotype, which was alleviated upon deletion of its N terminus. Biochemical assays demonstrated that acetylation of Pif1 stimulated its helicase, ATPase, and DNA-binding activities, whereas maintaining its substrate preferences. Limited proteolysis assays indicate that acetylation of Pif1 induces a conformational change that may account for its altered enzymatic properties. We propose that acetylation is involved in regulating of Pif1 activities, influencing a multitude of DNA transactions vital to the maintenance of genome integrity.
Rozprawy doktorskie na temat "DNA repair, helicase, G-quadruplex"
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Zhou, Jia. "Dna Glycosylases Remove Oxidized Base Damages From G-Quadruplex Dna Structures". ScholarWorks @ UVM, 2015. http://scholarworks.uvm.edu/graddis/529.
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The G-quadruplex DNA is a four-stranded DNA structure that is highly susceptible to oxidation due to its G-rich sequence and its structure. Oxidative DNA base damages can be mutagenic or lethal to cells if they are left unrepaired. The base excision repair (BER) pathway is the predominant pathway for repair of oxidized DNA bases. DNA glycosylases are the first enzymes in BER and are responsible for removing base lesions from DNA. How DNA glycosylases remove base lesions from duplex and single-stranded DNA has been intensively studied, while how they act on G-quadruplex DNA remains to be explored.
In Chapter II of this dissertation, we studied the glycosylase activity of the five mammalian DNA glycosylases (OGG1, NTH1, NEIL1, NEIL2 and mouse Neil3) on G-quadruplex DNA formed by telomere sequences that contain a single base lesion. We found that telomeric sequences that contain thymine glycol (Tg), 8-oxo-7,8-dihydroguanine (8-oxoG), guanidinohydantoin (Gh) or spiroiminodihydantoin (Sp) all formed the basket form of an antiparallel G-quadruplex DNA structure in Na+ solution. We also showed that no glycosylase was able to remove 8-oxoG from quadruplex DNA, while its further oxidation products, Sp and Gh, were good substrates for mNeil3 and NEIL1 in quadruplex DNA. In addition, mNeil3 is the only enzyme that removes Tg from quadruplex DNA and the glycosylase strongly prefers Tg in the telomere sequence context in both single-stranded and double-stranded DNA.
In Chapter III, we extended our study to telomeric G-quadruplex DNA in K+ solution and we also studied quadruplex DNA formed by promoter sequences. We found that 8-oxoG, Gh and Sp reduce the thermostability and alter the folding of telomeric quadruplex DNA in a location-dependent manner. Also, the NEIL1 and NEIL3 DNA glycosylases are able to remove hydantoin lesions but none of the glycosylases, including OGG1, are able to remove 8-oxoG from telomeric quadruplex DNA in K+ solution. Interestingly, NEIL1 or NEIL3 do not efficiently remove hydantoin lesions at the site that is most prone to oxidation in quadruplex DNA. However, hydantoin lesions at the same site in quadruplex DNA are removed much more rapidly by NEIL1, NEIL2 and NEIL3, when an extra telomere TTAGGG repeat is added to the commonly studied four-repeat quadruplex DNA to make it a five-repeat telomere quadruplex DNA. We also show that APE1 cleaves furan in selected positions in Na+-coordinated telomeric quadruplex DNA structures. We use promoter sequences of the VEGF and c-MYC genes as models to study promoter G-quadruplex DNA structures, and show that the NEIL glycosylases primarily remove Gh from Na+-coordinated antiparallel quadruplex DNA but not from K+-coordinated parallel quadruplex DNA containing VEGF or c-MYC promoter sequences.
Taken together, our data show that the NEIL DNA glycosylases may be involved in both telomere maintenance and gene regulation.
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Hodeib, Samar. "Real-time unfolding of DNA G-quadruplexes by helicases and polymerases". Thesis, Paris Sciences et Lettres (ComUE), 2017. http://www.theses.fr/2017PSLEE027/document.
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Les structures G-quadruplexes (G4) sont considérées comme des obstacles qui s’opposent à la progression du réplisome. Les séquences capables de former des G4 dans le génome humain se trouvent dans les régions d’ADN double brin au niveau des oncogènes et des proto-oncongènes et sur l’extrémité simple brin des télomères. La plupart des études biochimiques et biophysiques ont caractérisé les propriétés thermodynamiques des G4 en utilisant par exemple la température de fusion Tm pour déduire la thermodynamique de la formation/résolution du G4. Cependant, les expériences en solution donnent seulement une information indirecte concernant la dynamique du G4. Dans ce travail de thèse en molécule unique utilisant la technique des pinces magnétiques, nous avons pu caractériser la cinétique de la formation et résolution des G4s ainsi que la stabilité d’une structure G4 insérée dans une région d’ADN double brin : une situation qui ressemble aux G4 dans les promoteurs de gènes, où la séquence complémentaire est en compétition avec la formation de la structure de G4. Nous avons trouvé que le G4 télomérique a une très courte durée de vie (~20 s) et donc ce G4 se résout sans qu’une hélicase soit nécessaire. Au contraire, ce n’est pas le cas pour le G4 du c-MYC qui est très stable (~2h). Nous avons observé en temps réel la collision entre les hélicases et les polymérases et le G4 du c-MYC. Nous avons trouvé que l’hélicase Pif1 ouvre l’ADN puis résout le G4 après avoir effectué une pause et reprend l’ouverture de l’ADN, alors que l’hélicase RecQ et l’hélicase réplicative du bactériophage T4 ne peuvent pas le résoudre, mais peuvent le sauter. Nous avons aussi trouvé que la RPA ne peut pas résoudre le G4 du c-MYC. D’autre part, nous avons observé que la polyémrase du virus T4, la gp43, ainsi que la polymérase de T7, et la polymérase ε de la levure peuvent répliquer le G4 du c-MYC qui de façon étonnante ne constitue pas une barrière infranchissableG-quadruplex (G4) structures are considered as the major impediments for the replisome progression. The putative G4 forming sequences in the human genome are mostly located in the double-stranded DNA regions of oncogenes and proto-oncogenes and on the single-stranded overhangs of telomeres. Most of the biochemical and biophysical studies have characterized the G4 thermodynamics properties using melting temperature Tm as a proxy to infer thermodynamics of G4 folding/unfolding energetic. However, these thermodynamics properties give only indirect information about G4 dynamics. In this work, using single molecule magnetic tweezers technique, we first characterize the kinetics of folding and unfolding and thus the stability of a single G4 inserted in a dsDNA: a situation that mimics the G4s in promoters, where the complementary sequence competes with the G-rich structure. We find that the lifetime of telomeric G4 is short (~20 s) and thus that this G4 unfolds without the need of a helicase. This is not the case for the very stable c-MYC G4 (~2 hr). We observe in real time how helicases or polymerases behave as they collide with the c-MYC G4 on their track. We find that the Pif1 helicase unwinds dsDNA, resolves this G4 after pausing and resume unwinding, while RecQ helicase and the bacteriophage T4 replicative helicase do not resolve the G4 but may jump it. We also find that RPA does not unfold the c-MYC G4. Besides, we find that T4 bacteriophage gp43 polymerase, T7 polymerase and Yeast Pol ε can replicate the G4 which surprisingly does not appear as a major roadblock for them
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Pérez, González Daniel Cibrán. "Single-molecule studies of nucleic acid folding and nucleic acid-protein interactions". Thesis, University of St Andrews, 2017. http://hdl.handle.net/10023/12039.
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Nucleic acids and proteins, some of the building blocks of life, are not static structures but highly dynamic entities that need to interact with one another to meet cellular demands. The work presented in this thesis focuses on the application of highly sensitive fluorescence methods, both at ensemble and single-molecule level, to determine the dynamics and structure of specific biomolecular interactions with nanometer resolution and in temporal scales from nanoseconds to minutes, which includes most biologically relevant processes. The main aims of my PhD can be classified in three areas: i) exploring new fluorescent sensors with increased specificity for certain nucleic acid structures; ii) understanding how some of these nucleic acids sense the presence of small molecules in the cellular environment and trigger gene regulation by altering their structure; and iii) understanding how certain molecular machines, such as helicase proteins, are able to unwind the DNA double helix by using chemical energy in the form of ATP hydrolysis.
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Tuesuwan, Bodin 1975. "DNA cleavage chemistry of pyridinium-based heterocyclic skipped aza-enediynes and targeting SV40 large T-antigen G-quadruplex DNA helicase activity by G-quadruplex interactive agents". Thesis, 2007. http://hdl.handle.net/2152/3711.
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Two diverse works regarding DNA-Drug Interaction are presented here. The first portion deals with covalent interactions between compounds that are derivatives of heterocyclic aza-enediynes and DNA (conventional Watson-Crick base paired double stranded DNA) and the second is related to non-covalent interactions of these compounds with G-quadruplex DNA. The aza-enediynes have been studied for their ability to undergo aza-variants of the Bergman and Myers cyclizations, and the potential role of the ensuing diradicals in DNA cleavage chemistry. The aza-Myers-Saito cyclization of aza-enyne allenes that are derived from base-promoted isomerization of skipped aza-enediynes has been recently reported. In the first part of the dissertation, the synthesis and DNA cleavage chemistry of a series of pyridinium skipped aza-enediynes (2-alkynyl-Npropargyl pyridine salts) are reported. Efficient DNA cleavage requires the presence of the skipped aza-enediyne functionality, and optimal DNA cleavage occurs at basic pH. An optimized analog containing a p-methoxyphenyl substituent was prepared. Studies with radiolabeled DNA duplexes reveal that this analog generates nonselective frank DNA strand breaks, via deoxyribosyl 4'-hydrogen atom abstraction, and also leads to oxidation of DNA guanine bases. This is the first report of enediynelike radical-based DNA cleavage by an agent designed to undergo an alternative diradical-generating cyclization. The second part is based upon the growing evidence for G-quadruplex DNA structures in genomic DNA and the presumed need to resolve these structures for replication. A prototypical replicative helicase - SV40 large T-antigen (T-ag), a multifunctional protein with duplex DNA helicase activity is shown to also unwind G-quadruplex DNA structures. A series of G-quadruplex-interactive agents, particularly perylene diimide derivatives, is explored for inhibition of T-ag duplex and G-quadruplex DNA unwinding activities, and it is revealed that certain perylene diimides are both potent and selective inhibitors of the G-quadruplex DNA helicase activity of T-ag. Surface plasmon resonance and fluorescence spectroscopic Gquadruplex DNA binding studies of these T-ag G-quadruplex helicase inhibitors have been carried out, demonstrating the importance of attributes in addition to binding affinity for G-quadruplex DNA that may be important for inhibition. The identification of potent and selective inhibitors of the G-quadruplex helicase activity of T-ag provides tools for probing the specific role of this activity in SV40 replication.
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Lin, Shiao-Han, i 林筱涵. "Ⅰ Synthesis and Application of Photoaffinity Probes : Identification of Pregnenolone Binding Proteins and Study of G-Quadruplex Helicase Ⅱ Synthesis of Telomere-Directed DNA Alkylating Agents Based on Prodrug Concept". Thesis, 2013. http://ndltd.ncl.edu.tw/handle/85135478497642171722.
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碩士國立臺灣大學
化學研究所
101
The development of proteomics has opened up new horizons for the research of many diseases and drugs invention. Meanwhile, the related technology of affinity-based probes (AfBPs) provides more direct evidence about the mediation and regulation of protein in physiological condition. The actions of AfBPs are mainly based on molecular recognition, with the introducing of photoreactive groups (PGs) to achieve the specific covalent modification on protein. With the directing of different substrate, allowing scientists for the corresponding binding protein studies to understand the interaction between the protein and disease. This thesis is mainly divided into three parts: The first part is to study the embryonic-cell-movement related proteins. Our previous research indicated pregnenolone (PREG) can preserve the abundance of microtubules and effectively promote the development of embryonic cell, but the corresponding pregnenolone binding proteins (PBPs) is not clear. However, our recent studies found that pregnenolone probe (P5-NBPN) can effectively promote microtubule assembly, increase cell migration rate and specifically target to cytoplasmic linker protein (CLIP1, or CLIP -170). To validate the structural interaction about the binding mode and mechanism between pregnenolone and CLIP-170, we introduced the reactive groups at different positions on pregnenolone. At this point, We designed and synthesized the photoreactive probes (P5C20-NBPN) composed of pregnenolone as recognition unit, benzophenone as the photo cross-linker and a biotin as the reporter. Hope to compare the efficiency among these regio-affinity probes of pregnenolone on photolabeling experiments, and to understand more details about the binding mode, as the basis for drug development in the future. The second part is to study and discuss about G-quadruplex helicase. Many studies have demonstrated that the protein can maintain genomic stability, suppress inappropriate genetic recombination and inhibit of tumor progression, but still do not know about the mechanism of action. We designed and synthesized BMVC-DzN3, directing by the ligand of G-quadruplex. After reactive groups excited by irradiation, helicase is expected to be selectively labeling to obtain the direct binding evidence with G-quadruplex structures and explore its subsequent physiological functions. Although DNA-alkylated agents display excellent ability to inhibit cancer cell growing, but due to low selectivity, resulting in extremely serious side effects on the clinical application. In the third part, we hope to take advantage on molecular recognition and the concept of prodrug. BMVC equipped with DNA-alkylated agents - nitrogen mustard sheltered by phenylboronic ester were synthesized, named BMVC-Ak, to achieve high cytotoxicity toward cancer cells with good selectivity.
Części książek na temat "DNA repair, helicase, G-quadruplex"
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Granotier, Christine, i Francois D. "Differential Effects of the G-Quadruplex Ligand 360A in Human Normal and Cancer Cells". W DNA Repair and Human Health. InTech, 2011. http://dx.doi.org/10.5772/24130.
Pełny tekst źródłaStreszczenia konferencji na temat "DNA repair, helicase, G-quadruplex"
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Aparicio, S. "Abstract MS1-1: Targeting DNA repair deficiency in triple negative breast cancers (TNBC) with G-quadruplex stabilisers". W Abstracts: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.sabcs17-ms1-1.
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"G-quadruplex formed by the promoter region of the hTERT gene: structure-driven effects on DNA mismatch repair functions". W Bioinformatics of Genome Regulation and Structure/Systems Biology (BGRS/SB-2022) :. Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences, 2022. http://dx.doi.org/10.18699/sbb-2022-599.
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Hilton, John, Karen Gelmon, David Cescon, Anna Tinker, Derek Jonker, Rachel Goodwin, Scott Laurie i in. "Abstract PD4-02: Canadian cancer trials group trial IND.231: A phase 1 trial evaluating CX-5461, a novel first-in-class G-quadruplex stabilizer in patients with advanced solid tumors enriched for DNA-repair deficiencies". W Abstracts: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.sabcs19-pd4-02.
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