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Item Open Access THE ARABIDOPSIS THALIANA POLY(ADP-RIBOSE) POLYMERASES 1 AND 2 MODIFY DNA BY ADP-RIBOSYLATING TERMINAL PHOSPHATE RESIDUES(Frontiers Media, 2020-11-26) Taipakova, Sabira; Kuanbay, Aigerim; Saint-Pierre, Christine; Gasparutto, Didier; Baiken, Yeldar; Groisman, Regina; Ishchenko, Alexander A.; Saparbaev, Murat; Bissenbaev, Amangeldy K.Proteins from the poly(ADP-ribose) polymerase (PARP) family, such as PARP1 and PARP2, use NAD+ as a substrate to catalyze the synthesis of polymeric chains consisting of ADP-ribose units covalently attached to an acceptor molecule. PARP1 and PARP2 are viewed as DNA damage sensors that, upon binding to strand breaks, poly(ADP-ribosyl)ate themselves and nuclear acceptor proteins. The flowering plant Arabidopsis thaliana contains three genes encoding homologs of mammalian PARPs: atPARP1, atPARP2, and atPARP3. Both atPARP1 and atPARP2 contain poly(ADP-ribosyl)ating activity; however, it is unknown whether they could covalently modify DNA by ADP-ribosylating the strand break termini. Here, we report that similar to their mammalian counterparts, the plant atPARP1 and atPARP2 proteins ADP-ribosylate 5′-terminal phosphate residues in duplex DNA oligonucleotides and plasmid containing at least two closely spaced DNA strand breaks. AtPARP1 preferentially catalyzes covalent attachment of ADP-ribose units to the ends of recessed DNA duplexes containing 5′-phosphate, whereas atPARP2 preferentially ADP-ribosylates the nicked and gapped DNA duplexes containing the terminal 5′-phosphate. Similar to their mammalian counterparts, the plant PARP-catalyzed DNA ADP-ribosylation is particularly sensitive to the distance that separates two strand breaks in the same DNA molecule, 1.5 and 1 or 2 turns of helix for atPARP1 and atPARP2, respectively. PAR glycohydrolase (PARG) restored native DNA structure by hydrolyzing the PAR–DNA adducts generated by atPARPs. Biochemical and mass spectrometry analyses of the PAR–DNA adducts showed that atPARPs utilize phosphorylated DNA termini as an alternative to protein acceptor residues to catalyze PAR chain synthesis via phosphodiester bond formation between C1′ of ADP-ribose and a phosphate residue of the terminal nucleotide in DNA fragment. Taken together, these data establish the presence of a new type of DNA-modifying activity in Arabidopsis PARPs, suggesting a possible role of DNA ADP-ribosylation in DNA damage signaling and repair of terrestrial plants.Item Open Access DNA-HISTONE CROSS-LINKS: FORMATION AND REPAIR(Frontiers Media, 2020-12-21) Pachva, Manideep C.; Kisselev, Alexei F.; Matkarimov, Bakhyt T.; Saparbaev, Murat; Groisman, ReginaThe nucleosome is a stretch of DNA wrapped around a histone octamer. Electrostatic interactions and hydrogen bonds between histones and DNA are vital for the stable organization of nucleosome core particles, and for the folding of chromatin into more compact structures, which regulate gene expression via controlled access to DNA. As a drawback of tight association, under genotoxic stress, DNA can accidentally crosslink to histone in a covalent manner, generating a highly toxic DNA-histone cross-link (DHC). DHC is a bulky lesion that can impede DNA transcription, replication, and repair, often with lethal consequences. The chemotherapeutic agent cisplatin, as well as ionizing and ultraviolet irradiations and endogenously occurring reactive aldehydes, generate DHCs by forming either stable or transient covalent bonds between DNA and side-chain amino groups of histone lysine residues. The mechanisms of DHC repair start to unravel, and certain common principles of DNA-protein cross-link (DPC) repair mechanisms that participate in the removal of cross-linked histones from DNA have been described. In general, DPC is removed via a two-step repair mechanism. First, cross-linked proteins are degraded by specific DPC proteases or by the proteasome, relieving steric hindrance. Second, the remaining DNA-peptide cross-links are eliminated in various DNA repair pathways. Delineating the molecular mechanisms of DHC repair would help target specific DNA repair proteins for therapeutic intervention to combat tumor resistance to chemotherapy and radiotherapy.Item Open Access The Human DNA glycosylases NEIL1 and NEIL3 Excise Psoralen-Induced DNA-DNA Cross-Links in a Four-Stranded DNA Structure(Nature Research, 2017) Martin, Peter R.; Couvé, Sophie; Zutterling, Caroline; Albelazi, Mustafa S.; Groisman, Regina; Matkarimov, Bakhyt T.; Parsons, Jason L.; Elder, Rhoderick H.; Saparbaev, Murat K.Interstrand cross-links (ICLs) are highly cytotoxic DNA lesions that block DNA replication and transcription by preventing strand separation. Previously, we demonstrated that the bacterial and human DNA glycosylases Nei and NEIL1 excise unhooked psoralen-derived ICLs in three-stranded DNA via hydrolysis of the glycosidic bond between the crosslinked base and deoxyribose sugar. Furthermore, NEIL3 from Xenopus laevis has been shown to cleave psoralen- and abasic site-induced ICLs in Xenopus egg extracts. Here we report that human NEIL3 cleaves psoralen-induced DNA-DNA cross-links in three-stranded and four-stranded DNA substrates to generate unhooked DNA fragments containing either an abasic site or a psoralen-thymine monoadduct. Furthermore, while Nei and NEIL1 also cleave a psoralen-induced four-stranded DNA substrate to generate two unhooked DNA duplexes with a nick, NEIL3 targets both DNA strands in the ICL without generating single-strand breaks. The DNA substrate specificities of these Nei-like enzymes imply the occurrence of long uninterrupted three- and four-stranded crosslinked DNA-DNA structures that may originate in vivo from DNA replication fork bypass of an ICL. In conclusion, the Nei-like DNA glycosylases unhook psoralen-derived ICLs in various DNA structures via a genuine repair mechanism in which complex DNA lesions can be removed without generation of highly toxic double-strand breaks.Item Open Access Insight into DNA substrate specificity of PARP1-catalysed DNA poly(ADP-ribosyl)ation(Springer Nature, 2020-02-28) Matkarimov, Bakhyt T.; Matta, Elie; Kiribayeva, Assel; Khassenov, Bekbolat; Ishchenko, Alexander A.DNA-dependent poly(ADP-ribose) polymerases (PARPs) PARP1, PARP2 and PARP3 act as DNA break sensors signalling DNA damage. Upon detecting DNA damage, these PARPs use nicotine adenine dinucleotide as a substrate to synthesise a monomer or polymer of ADP-ribose (MAR or PAR, respectively) covalently attached to the acceptor residue of target proteins. Recently, it was demonstrated that PARP1–3 proteins can directly ADP-ribosylate DNA breaks by attaching MAR and PAR moieties to terminal phosphates. Nevertheless, little is still known about the mechanisms governing substrate recognition and specificity of PARP1, which accounts for most of cellular PARylation activity. Here, we characterised PARP1-mediated DNA PARylation of DNA duplexes containing various types of breaks at different positions. The 3′-terminal phosphate residue at double-strand DNA break ends served as a major acceptor site for PARP1-catalysed PARylation depending on the orientation and distance between DNA strand breaks in a single DNA molecule. A preference for ADP-ribosylation of DNA molecules containing 3′-terminal phosphate over PARP1 auto-ADP-ribosylation was observed, and a model of DNA modification by PARP1 was proposed. Similar results were obtained with purified recombinant PARP1 and HeLa cell-free extracts. Thus, the biological effects of PARP-mediated ADP-ribosylation may strongly depend on the configuration of complex DNA strand breaks.Item Open Access Characterization of DNA ADP-ribosyltransferase activities of PARP2 and PARP3: new insights into DNA ADP-ribosylation(Oxford University Press, 2018-01) Zarkovic, Gabriella; Belousova, Ekaterina; Talhaoui, Ibtissam; Saint-Pierre, Christine; Kutuzov, Mikhail M.; Matkarimov, Bakhyt; Biard, Denis; Gasparutto, Didier; Lavrik, Olga I.; Ishchenko, Alexander A.Poly(ADP-ribose) polymerases (PARPs) act as DNA break sensors and catalyze the synthesis of polymers of ADP-ribose (PAR) covalently attached to acceptor proteins at DNA damage sites. It has been demonstrated that both mammalian PARP1 and PARP2 PARylate double-strand break termini in DNA oligonucleotide duplexes in vitro. Here, we show that mammalian PARP2 and PARP3 can PARylate and mono(ADP-ribosyl)ate (MARylate), respectively, 5′- and 3′-terminal phosphate residues at double- and single-strand break termini of a DNA molecule containing multiple strand breaks. PARP3-catalyzed DNA MARylation can be considered a new type of reversible post-replicative DNA modification. According to DNA substrate specificity of PARP3 and PARP2, we propose a putative mechanistic model of PARP-catalyzed strand break–oriented ADP-ribosylation of DNA termini. Notably, PARP-mediated DNA ADP-ribosylation can be more effective than PARPs’ auto-ADP-ribosylation depending on the DNA substrates and reaction conditions used. Finally, we show an effective PARP3- or PARP2-catalyzed ADP-ribosylation of high-molecular-weight (∼3-kb) DNA molecules, PARP-mediated DNA PARylation in cell-free extracts and a persisting signal of anti-PAR antibodies in a serially purified genomic DNA from bleomycin-treated poly(ADP-ribose) glycohydrolase-depleted HeLa cells. These results suggest that certain types of complex DNA breaks can be effectively ADP-ribosylated by PARPs in cellular response to DNA damage.Item Open Access Determining the optimal number of independent components for reproducible transcriptomic data analysis(BioMed Central, 2017) Kairov, Ulykbek; Cantini, Laura; Greco, Alessandro; Molkenov, Askhat; Czerwinska, Urszula; Barillot, Emmanuel; Zinovyev, AndreiBackground: Independent Component Analysis (ICA) is a method that models gene expression data as an action of a set of statistically independent hidden factors. The output of ICA depends on a fundamental parameter: the number of components (factors) to compute. The optimal choice of this parameter, related to determining the effective data dimension, remains an open question in the application of blind source separation techniques to transcriptomic data.Results: Here we address the question of optimizing the number of statistically independent components in the analysis of transcriptomic data for reproducibility of the components in multiple runs of ICA (within the same or within varying effective dimensions) and in multiple independent datasets. To this end, we introduce ranking of independent components based on their stability in multiple ICA computation runs and define a distinguished number of components (Most Stable Transcriptome Dimension, MSTD) corresponding to the point of the qualitative change of the stability profile. Based on a large body of data, we demonstrate that a sufficient number of dimensions is required for biological interpretability of the ICA decomposition and that the most stable components with ranks below MSTD have more chances to be reproduced in independent studies compared to the less stable ones. At the same time, we show that a transcriptomics dataset can be reduced to a relatively high number of dimensions without losing the interpretability of ICA, even though higher dimensions give rise to components driven by small gene sets. Conclusions: We suggest a protocol of ICA application to transcriptomics data with a possibility of prioritizing components with respect to their reproducibility that strengthens the biological interpretation. Computing too few components (much less than MSTD) is not optimal for interpretability of the results. The components ranked within MSTD range have more chances to be reproduced in independent studies.Item Open Access Aberrant DNA glycosylase-initiated repair pathway of free radicals induced DNA damage: implications for age-related diseases and natural aging(Biopolymers and Cell. doi: http://dx.doi.org/10.7124/bc.000943, 2017) Matkarimov, B.; Saparbaev, M.Aerobic cellular respiration generates reactive oxygen species (ROS), which can damage macro-molecules including lipids, proteins and DNA. It was proposed that aging is a consequence of accumulation of naturally occurring unrepaired oxidative DNA damage. In human cells, approximately 2000 to 8000 DNA lesions occur per hour in each cell, i.e. 40000 to 200000 per cell per day. DNA repair systems are able to discriminate between regular and modified bases. For example, DNA glycosylases specifically recognize and excise damaged bases among vast majority of regular bases in the base excision repair (BER) pathway. However, mismatched pairs between two regular bases occur due to spontaneous conversion of 5-methylcytosine to thymine and DNA polymerase errors during replication. To counteract these mutagenic threats to genome stability, cells evolved special DNA repair systems that target the non-damaged DNA strand in a duplex to remove mismatched regular DNA bases. Base excision repair (BER) and mismatch repair (MMR) pathways initiated by mismatch-specific adenine- and thymine-DNA glycosylases (MutY/MUTYH and TDG/MBD4, respectively) can recognize and remove normal DNA bases in mismatched DNA duplexes. Under certain circumstances in DNA repair deficient cells bacterial MutY and human TDG can act in an aberrant manner: MutY and TDG remove Adenine and Thymine opposite to misincorporated 8-oxoguanine and damaged Adenine, respectively. These unusual activities lead either to mutations or futile DNA repair, thus indicating that the DNA repair pathways which target non-damaged DNA strand can act in an aberrant manner and introduce genome instability in the presence of unrepaired DNA lesions. Both accumulation of oxidative DNA damage in cells and the aberrant DNA repair can contribute to cancer, brain disorders and premature senescence.Item Open Access Самоорганизация дипептидного производного в гидрогели и криогели для биомедицинских целей(RAM Trade company, 2016) Берилло, ДмитрийСпособность биомолекул к молекулярному узнаванию в природных системах выработана в процессе эволюции. Недавние исследования выявили библиотеки пептидов с селективным сродством к самоструктурированию (самоорганизацией или самосборки) в супрамолекулярные структуры (нанотрубки, нанофибриллы) для создания новых искусственных биоразлагаемых материалов...Item Open Access Включение важнейших многочастичных взаимодействий в силовое поле AMBER и оптимизация энергетических параметров обновленного поля(Математическая биология и биоинформатика, 2015) Гарбузинский (Garbuzinskiy), С.А. ( S.A.); Маткаримов (Matkarimov), Б.Т. (B.Т.); Финкельштейн ( Finkelstein), А.В. (A.V.)Разработана новая функциональная форма для силового поля невалентных взаимодействий, учитывающая, наряду с традиционными членами, как наведенную парциальными зарядами поляризацию всех атомов, так и трехчастичные дисперсионные взаимодействия «атом – валентная связь». Соответствующие новые члены добавлены к стандартному силовому полю AMBER. В рамках этой единой функциональной формы силового поля оптимизированы, с использованием данных по молекулярным кристаллам, параметры всех типов невалентных взаимодействий. Показано заметное увеличение коэффициента корреляции между рассчитанной и экспериментально определенной энергией когезии молекул в молекулярных кристаллах. A new functional form for force field of non-covalent interactions is developed. Besides traditional members, it involves induced (by partial charges) polarization of all atoms as well as three-particle dispersion interactions of atoms with covalent bonds. The corresponding new members are added to a standard AMBER force field. Within this unified functional form of the force field, parameters of all types of non-covalent interactions are optimized using data on molecular crystals. A noticeable increase in correlation coefficient between calculated and experimental energy of cohesion of molecules in molecular crystals is shown.Item Open Access Включение важнейших многочастичных взаимодействий в силовое поле АМБЕР и применение обновленного поля к молекулярно-динамическим расчетам(Математическая биология и биоинформатика, 2015) Маткаримов (Matkarimov), Б.Т. (Bakhyt); Балабаев (Balabaev), Н.К.(N.K.); Гарбузинский (Garbuzinskiy), С.А. ( S.A.); Галзитская (Galzitskaya), О.В. (O.V.); Глякина (Glyakina), А.В. (A.V.); Финкельштейн ( Finkelstein), А.В. (A.V.); Маткаримов (Matkarimov), Б.Т. (B.Т.)Выведены формулы для расчета потенциалов и сил в новом силовом поле невалентных взаимодействий, включающем, наряду с традиционными членами, наведенную парциальными зарядами поляризацию всех атомов и трехчастичные дисперсионные взаимодействия «атом – валентная связь». Соответствующие новые члены добавлены к стандартному силовому полю АМБЕР. Проведены молекулярно-динамические расчеты с использованием обновленного силового поля. Показано, что добавленные, физически разумные члены не сильно замедляют молекулярно-динамическое моделирование, несмотря на то, что они учитывают важнейшие трехчастичные взаимодействия. Formulas for calculation of energy and forces in the new force field of non bonded interactions including along with traditional members, the polarization, induced by partial atomic charges, and three-particle dispersive interactions of the atoms with covalent bonds are received. The corresponding new members are added to a standard AMBER force field. Molecular dynamics calculations with the use of the updated force field are carried out. It is shown that additional physically reasonable members, taking into account the major three-particle interactions, not strongly slow down molecular dynamics simulation.Item Open Access Aberrant repair initiated by mismatch-specific thymine-DNA glycosylases provides a mechanism for the mutational bias observed in CpG islands(Nucleic Acids Research, 2014-04-01) Talhaoui, Ibtissam; Couve, Sophie; Gros, Laurent; Ishchenko, Alexander A.; Matkarimov, Bakhyt; Saparbaev, Murat K.The human thymine-DNA glycosylase (TDG) initiates the base excision repair (BER) pathway to remove spontaneous and induced DNA base damage. It was first biochemically characterized for its ability to remove T mispaired with G in CpG context. TDG is involved in the epigenetic regulation of gene expressions by protecting CpG-rich promoters from de novo DNA methylation. Here we demonstrate that TDG initiates aberrant repair by excising T when it is paired with a damaged adenine residue in DNA duplex. TDG targets the non-damaged DNA strand and efficiently excises T opposite of hypoxanthine (Hx), 1,N6-ethenoadenine, 7,8-dihydro-8-oxoadenine and abasic site in TpG/CpX context, where X is a modified residue. In vitro reconstitution of BER with duplex DNA containing Hx•T pair and TDG results in incorporation of cytosine across Hx. Furthermore, analysis of the mutation spectra inferred from single nucleotide polymorphisms in human population revealed a highly biased mutation pattern within CpG islands (CGIs), with enhanced mutation rate at CpA and TpG sites. These findings demonstrate that under experimental conditions used TDG catalyzes sequence context-dependent aberrant removal of thymine, which results in TpG, CpA→CpGmutations, thus providing a plausible mechanism for the putative evolutionary origin of the CGIs in mammalian genomes.Item Open Access Oxidatively Generated Guanine(C8)-Thymine(N3) Intrastrand Cross-links in Double-stranded DNA Are Repaired by Base Excision Repair Pathways*(The Journal of Biological Chemistry, 2015-04-15) Talhaoui, Ibtissam; Shafirovich, Vladimir; Liu, Zhi; Saint-Pierre, Christine; Akishev, Zhiger; Matkarimov, Bakhyt T.; Gasparutto, Didier; Geacintov, Nicholas E.; Saparbaev, MuratOxidatively generated guanine radical cations in DNA can undergo various nucleophilic reactions including the formation of C8-guanine cross-links with adjacent or nearby N3-thymines in DNA in the presence of O2. The G*[C8-N3]T* lesions have been identified in the DNA of human cells exposed to oxidative stress, and are most likely genotoxic if not removed by cellular defense mechanisms. It has been shown that the G*[C8-N3]T* lesions are substrates of nucleotide excision repair in human cell extracts. Cleavage at the sites of the lesions was also observed but not further investigated (Ding et al. (2012) Nucleic Acids Res. 40, 2506–2517). Using a panel of eukaryotic and prokaryotic bifunctional DNA glycosylases/lyases (NEIL1, Nei, Fpg, Nth, and NTH1) and apurinic/apyrimidinic (AP) endonucleases (Apn1, APE1, and Nfo), the analysis of cleavage fragments by PAGE and MALDI-TOF/MS show that the G*[C8-N3]T* lesions in 17-mer duplexes are incised on either side of G*, that none of the recovered cleavage fragments contain G*, and that T* is converted to a normal T in the 3′-fragment cleavage products. The abilities of the DNA glycosylases to incise the DNA strand adjacent to G*, while this base is initially cross-linked with T*, is a surprising observation and an indication of the versatility of these base excision repair proteins.Item Open Access Role of viruses in the development of breast cancer(Infectious Agents and Cancer, 2013-09-02) Alibek, Kenneth; Kakpenova, Ainur; Mussabekova, Assel; Sypabekova, Marzhan; Karatayeva, NargisThe most common cancer worldwide among women is breast cancer. The initiation, promotion, and progression of this cancer result from both internal and external factors. The International Agency for Research on Cancer stated that 18-20% of cancers are linked to infection, and the list of definite, probable, and possible carcinogenic agents is growing each year. Among them, biological carcinogens play a significant role. In this review, data covering infection-associated breast and lung cancers are discussed and presented as possible involvements as pathogens in cancer. Because carcinogenesis is a multistep process with several contributing factors, we evaluated to what extent infection is significant, and concluded that members of the herpesvirus, polyomavirus, papillomavirus, and retrovirus families definitely associate with breast cancer. Detailed studies of viral mechanisms support this conclusion, but have presented problems with experimental settings. It is apparent that more effort needs to be devoted to assessing the role of these viruses in carcinogenesis, by characterizing additional confounding and synergistic effects of carcinogenic factors. We propose that preventing and treating infections may possibly stop or even eliminate certain types of cancers.Item Open Access The role of infectious agents in urogenital cancers(BioMed Central, 2012-12-03) Alibek, Kenneth; Karatayeva, Nargis; Bekniyazov, IldarSince the late 1990s, infectious agents have been thought to play a role in the pathogenesis of approximately 15% of cancers. It is now widely accepted that infection of stomach tissue with the bacteria Helicobacter pylori is an important cause of stomach adenocarcinoma. In addition, oncogenic viruses, such as papilloma viruses, herpes viruses, and hepadnaviruses are strongly associated with increased risk of cervical cancer, lymphomas, liver cancer, amongst others. However, in the scientific community the percentage of cancers caused by pathogens is believed to be far higher than 15%. A significant volume of data collected to date show an association between infectious agents and urogenital cancers. These agents include Chlamydia trachomatis, Neisseria gonorrhoea, Mycoplasma genitalium and certain viruses that have been implicated in ovarian cancer.Item Open Access Синтез, строение и свойства гидразидов β-аминопропановой кислоты и их производных(КазНУ им. аль-Фараби, 2010) Berillo (Берилло), Dmitriy (Дмитрий)Настоящая работа посвящена комплексному исследованию в области синтеза потенциально биологически активных веществ на основе гидразидов и нитрилов α-( и β-)-аминопропановых кислот, установлению закономерностей их гетероциклизации и изучению биологической активности новых производных гидразидов и нитрилов α-( и β-)- аминокислот.Item Open Access Synthesis of trans-porphyrin dimers for nonlinear optics(“NURIS”, Nazarbayev University, Astana, Kazakhstan, 2014) Baptayev, Bakhytzhan; Tauanov, Zhandos; Bissengaliyeva, Moldir; Zhakiyeva, Zhanar; Berillo, Dmitriy; Adilov, SalimgereyFollowing the development of the idea of octupolar molecules as nonlinear optical materials a variety of compounds have been reported. Trans-porphyrins have a great potential to self-order into octupolar symmetry. Nonlinear optical properties can be tuned by using strong donor-acceptor groups in porphyrins as well as extention of conjugation. Here we report the syntheses of trans-A2D2-porphyrins and their dimerization into cubic octupoles by lanthanides and organic bidentate ligands. Bulky groups are employed to induce non-centrosymmetric eclipsed or staggered conformations. Effect of donor acceptor groups, dimerization conditions and crystal packing of dimers are studied.