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Babkin I.V.,Institute of Chemical Biology and Fundamental Medicine
Intervirology | Year: 2011

Objectives: The goal of this work was to study the evolutionary history of the vertebrate poxviruses using the Bayesian relaxed clock and a large set of highly conserved vitally important viral genes. Methods: Phylogenetic analysis was performed by the maximum likelihood method using the Paup program. The dating method of Bayes, realized in the Multidivtime, was made. Results: The rate of poxviral evolution is estimated as 0.5-7 × 10 -6 nucleotide substitutions per site per year. We inferred that the modern viruses of the genus Avipoxvirus diverged from the ancestor nearly 249 ± 69 thousand years ago (Tya). The progenitor of the genus Orthopoxvirus separated approximately 166 ± 43 Tya. The separation of the forebear of the genus Leporipoxvirus took place about 137 ± 35 Tya. The next to diverge was the ancestor of the genus Yatapoxvirus. The progenitor of Capripoxvirus and Suipoxvirus diverged 111 ± 29 Tya. Conclusion: The evolutionary analysis based on the historical data and utilizing the Bayesian relaxed clock allowed us to determine the molecular evolution rates of the AT-rich genomes of the vertebrate poxviruses and assess the times of their emergences. Involvement of a large set of the conserved genes controlled by stabilizing selection allowed us to perform molecular dating of the vertebrate poxvirus history. Copyright © 2011 S. Karger AG, Basel.

Moor N.,Institute of Chemical Biology and Fundamental Medicine | Klipcan L.,Weizmann Institute of Science | Safro M.G.,Weizmann Institute of Science
Chemistry and Biology | Year: 2011

Aminoacyl-tRNA synthetases exert control over the accuracy of translation by selective pairing the correct amino acids with their cognate tRNAs, and proofreading the misacylated products. Here we show that three existing, structurally different phenylalanyl-tRNA synthetases-human mitochondrial (HsmtPheRS), human cytoplasmic (HsctPheRS), and eubacterial from Thermus thermophilus (TtPheRS), catalyze mischarging of tRNA Phe with an oxidized analog of tyrosine-L-dopa. The lowest level of L-dopa discrimination over the cognate amino acid, exhibited by HsmtPheRS, is comparable to that of tyrosyl-tRNA synthetase. HsmtPheRS and TtPheRS complexes with L-dopa revealed in the active sites an electron density shaping this ligand. HsctPheRS and TtPheRS possessing editing activity are capable of hydrolyzing the exogenous L-dopa-tRNA Phe as efficiently as Tyr-tRNA Phe. However, editing activity of PheRS does not guarantee reduction of the aminoacylation error rate to escape misincorporation of L-dopa into polypeptide chains. © 2011 Elsevier Ltd All rights reserved.

Finarov I.,Weizmann Institute of Science | Moor N.,Institute of Chemical Biology and Fundamental Medicine | Kessler N.,Weizmann Institute of Science | Klipcan L.,Weizmann Institute of Science | Safro M.G.,Weizmann Institute of Science
Structure | Year: 2010

The existence of three types of phenylalanyl-tRNA synthetase (PheRS), bacterial (αβ)2, eukaryotic/archaeal cytosolic (αβ)2, and mitochondrial α, is a prominent example of structural diversity within the aaRS family. PheRSs have considerably diverged in primary sequences, domain compositions, and subunit organizations. Loss of the anticodon-binding domain B8 in human cytosolic PheRS (hcPheRS) is indicative of variations in the tRNAPhe binding and recognition as compared to bacterial PheRSs. We report herein the crystal structure of hcPheRS in complex with phenylalanine at 3.3 Å resolution. A novel structural module has been revealed at the N terminus of the α subunit. It stretches out into the solvent of ∼80 Å and is made up of three structural domains (DBDs) possessing DNA-binding fold. The dramatic reduction of aminoacylation activity for truncated N terminus variants coupled with structural data and tRNA-docking model testify that DBDs play crucial role in hcPheRS activity. © 2010 Elsevier Ltd. All rights reserved.

Lebedeva N.A.,Institute of Chemical Biology and Fundamental Medicine | Rechkunova N.I.,Novosibirsk State University | Ishchenko A.A.,University Paris - Sud | Saparbaev M.,University Paris - Sud | Lavrik O.I.,Novosibirsk State University
DNA Repair | Year: 2013

The mechanism of hydrolysis of the apurinic/apyrimidinic (AP) site and its synthetic analogs by using tyrosyl-DNA phosphodiesterase 1 (Tdp1) was analyzed. Tdp1 catalyzes the cleavage of AP site and the synthetic analog of the AP site, 3-hydroxy-2(hydroxymethyl)-tetrahydrofuran (THF), in DNA by hydrolysis of the phosphodiester bond between the substituent and 5' adjacent phosphate. The product of Tdp1 cleavage in the case of the AP site is unstable and is hydrolyzed with the formation of 3'- and 5'-margin phosphates. The following repair demands the ordered action of polynucleotide kinase phosphorylase, with XRCC1, DNA polymerase β, and DNA ligase. In the case of THF, Tdp1 generates break with the 5'-THF and the 3'-phosphate termini. Tdp1 is also able to effectively cleave non-nucleotide insertions in DNA, decanediol and diethyleneglycol moieties by the same mechanism as in the case of THF cleavage. The efficiency of Tdp1 catalyzed hydrolysis of AP-site analog correlates with the DNA helix distortion induced by the substituent. The following repair of 5'-THF and other AP-site analogs can be processed by the long-patch base excision repair pathway. © 2013 Elsevier B.V.

Belousova E.A.,Institute of Chemical Biology and Fundamental Medicine | Lavrik O.I.,Novosibirsk State University
DNA Repair | Year: 2015

Among the set of mammalian DNA polymerases, DNA polymerases belonging to the X and Y families have a special place. The majority of these enzymes are involved in repair, including base excision repair and non-homologous end joining. Some of them play a crucial role during the specific process which is referred to as translesion synthesis (TLS). TLS intends for the cell surviving during the replication of damaged DNA templates. Additionally, specific activities of TLS-polymerases have to be useful for repair of double-stranded clustered lesions: if the synthesis is proceeded via base excision repair process, the role of DNA polymerases β or λ will be important. In this review we discussed the biochemical properties and functional relevance of X family DNA polymerases β and λ. © 2015 Elsevier B.V.

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