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1.
The structural and energetic properties of native and oxidized telomeric complexes were defined by means of molecular dynamic (MD) simulations. As a starting point, the experimental conformation of B-DNA d(GpTpTpApGpGpGpTpTpApGpGpG) oligomer bound to human protein telomeric repeat binding factor 1 (TRF1) was used. The influence on the stability of the telomeric complex of the presence of 8-oxoguanine (8oxoG) in the central telomeric triad (CTT) was estimated based on trajectories collected during 130 ns MD runs. The data obtained indicate that the system analyzed is highly sensitive to the presence of oxidative damage in the CTT of the B-DNA telomeric sequence. The most important changes were observed in the immediate vicinity of the 8-oxoguanine molecule. The significantly higher mobility of arginine 425 interacting directly with the oxidized guanine molecule has a large influence on the structural, dynamic and energetic properties of neighboring amino acids. Local changes observed for individual hydrogen bonded interactions localized in the major groove of B-DNA also have significant impact on the properties of hydrophobic clusters, which are the second type of force responsible for stability of the studied bio-system. All the changes reported in detail here unambiguously indicate a significant decrease in telomer binding affinity after oxidation. 相似文献
2.
The molecular dynamics as well as ab initio MP2/6-31G(d = 0.25) single point calculations were performed for native and oxidized B-DNA telomeric fragments. The structural,
dynamic, energetic and electrostatic properties along with frontier orbitals distribution were described for the central triad
consisting of three guanine molecules in its canonical or oxidized forms. Although the average structural parameters characterizing
all of the studied telomere fragments are close each to other, the significant consequence on angular and displacement flexibilities
are observed. Namely, the increase of mutual displacement of two successive base pairs along either axis and increase of the
rotation of two bases of opposite strand are main dynamic consequences of presence of 8-oxo-guanine in the central triad of
telomeric B-DNA. Besides, the significant increase of stacking energies in case of 8-oxo-guanine were found. Furthermore,
the guanine pattern visible from the major groove may be described as donor-acceptor-acceptor formed by H8-N7-O6 atoms, respectively. To the contrary the presence of 8-oxo-guanine changes the electrostatic properties of the major groove
into acceptor-donor-acceptor coming from O8-H7-O6 atoms. This results in significant alteration of ESP characteristics. Finally, the molecular orbital properties are also
significantly affected by oxidation of telomeric B-DNA fragments. All these factors contribute to decrease of binding of telomere
proteins.
Figure The consequences of guanine oxidation in central GGG telomeric triad on electrostatic properties of CCGTACTT-A1G2G3G4T5T6-AGGGTT-AACA telomere fragment
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
3.
Telomeres are nucleoprotein complexes at the ends of linear chromosomes in eukaryotes, and are essential in preventing chromosome termini from being recognized as broken DNA ends. Telomere shortening has been linked to cellular senescence and human aging, with oxidative stress as a major contributing factor. 7,8-Dihydro-8-oxogaunine (8-oxodG) is one of the most abundant oxidative guanine lesions, and 8-oxoguanine DNA glycosylase (OGG1) is involved in its removal. In this study, we examined if telomeric DNA is particularly susceptible to oxidative base damage and if telomere-specific factors affect the incision of oxidized guanines by OGG1. We demonstrated that telomeric TTAGGG repeats were more prone to oxidative base damage and repaired less efficiently than non-telomeric TG repeats in vivo. We also showed that the 8-oxodG-incision activity of OGG1 is similar in telomeric and non-telomeric double-stranded substrates. In addition, telomere repeat binding factors TRF1 and TRF2 do not impair OGG1 incision activity. Yet, 8-oxodG in some telomere structures (e.g., fork-opening, 3'-overhang, and D-loop) were less effectively excised by OGG1, depending upon its position in these substrates. Collectively, our data indicate that the sequence context of telomere repeats and certain telomere configurations may contribute to telomere vulnerability to oxidative DNA damage processing. 相似文献
4.
Piotr Cysewski 《Journal of molecular modeling》2010,16(11):1721-1729
Non-additivity of base-base interactions in all ten possible model dinucleotide steps were analyzed on MP2/aug-cc-pvDZ quantum
chemistry level. Conformations of four nucleobases exactly matched to ones occurring in B-DNA crystals. In most of thw 162
analyzed tetramers both three- and four-body contributions are negligible except for d(GpG) steps. However, in these dinucleotides
both contributions are always of opposite signs and in all cases the sum of all non-additive part of intermolecular interactions
do not exceed 2.6 kcal mol-1. This stands for less than 5% of the overall binding energy of dinucleotide steps. Also replacements of guanine with 8-oxoguanine
in d(GpG) systems introduces non-additivity of the same magnitude as for canonical dinucleotides. It is observed linear relationships
between values of total binding energy obtained in the tetramer basis set and estimated energy exclusively in dimers basis
sets with assumption of pairwise additivities. For all analyzed dinucleotides steps there are also linear correlations between
amount of non-additive contributions and magnitude of pairs interactions. Based on differences in electrostatic contribution
to the total binding energy of four nucleobases and polarity of dinucleotide steps three distinct classes of dinucleotide
steps were identified. 相似文献
5.
Piotr Cysewski 《Journal of molecular modeling》2009,15(6):597-606
The energies of intra- and inter-strand stacking interactions in model d(GpC) and d(CpG) two-base-pair steps were estimated
by MP2/aug-cc-pVDZ single point calculations corrected for basis superposition errors. The stacked two-nucleobase pairs were
constructed using experimental values of base pair and base step parameters taken from Nucleic Acid Database (). Three distinct polymorphic forms were analysed, namely A-, B- and Z-DNA. The applied methodology enables statistical analysis
of structural and energetic diversities. The structural relationships between polymorphic forms are quite complex and depend
on the sequence of pairs. The variability of parameters such as shift and tilt is almost the same irrespective of the polymorphic form and sequence of steps analysed. In contrast, shift and twist distributions easily discriminate all three polymorphic forms of DNA. Interestingly, despite significant structural diversities,
the energies of the most frequent energy ranges are comparable irrespective of the polymorphic form and base sequence. There
was observed compensation of inter- and intra-strand interactions, especially for d(GpC) and d(CpG) steps found in A- and
B-DNA. Thus, among many other roles, these pairs act as a kind of energetic buffer, balancing the double helix.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
6.
7.
Functional subdomain in the ankyrin domain of tankyrase 1 required for poly(ADP-ribosyl)ation of TRF1 and telomere elongation
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In human cells, telomere elongation by telomerase is repressed in cis by the telomeric protein TRF1. Tankyrase 1 binds TRF1 via its ankyrin domain and poly(ADP-ribosyl)ates it. Overexpression of tankyrase 1 in telomerase-positive cells releases TRF1 from telomeres, resulting in telomere elongation. The tankyrase 1 ankyrin domain is classified into five conserved subdomains, ARCs (ankyrin repeat clusters) I to V. Here, we investigated the biological significance of the ARCs. First, each ARC worked as an independent binding site for TRF1. Second, ARCs II to V recognized the N-terminal acidic domain of TRF1 whereas ARC I bound a discrete site between the homodimerization and the Myb-like domains of TRF1. Inactivation of TRF1 binding in the C-terminal ARC, ARC V, either by deletion or point mutation, significantly reduced the ability of tankyrase 1 to poly(ADP-ribosyl)ate TRF1, release TRF1 from telomeres, and elongate telomeres. In contrast, other ARCs, ARC II and/or IV, inactivated by point mutations still retained the biological function of tankyrase 1. On the other hand, ARC V per se was not sufficient for telomere elongation, suggesting a structural role for multiple ARCs. This work provides evidence that specific ARC-TRF1 interactions play roles in the essential catalytic function of tankyrase 1. 相似文献
8.
《Bioorganic & medicinal chemistry letters》2020,30(21):127401
Telomeric repeat binding factor 2 (TRF2) plays an important role in protecting telomeres from being recognized as DNA breaks. TRF2 performs its telomere protecting functions partially by recruiting a number of accessory proteins to telomeres through its TRF homology (TFRH) domain. Identification of small molecular compounds which can bind to the TRFH domain of TRF2 and block the interactions between TRF2 and its associated proteins is crucial for elucidating the molecular mechanisms of these protein–protein interactions. Using a previously identified peptidic mimetic of ApolloTBM as a lead compound, we designed and synthesized a series of novel TRF2 inhibitors by non-peptidic modifications of the N-terminal residues. These compounds can maintain the binding affinities to TRF2 but have much reduced peptidic characteristics compared to the lead compound. 相似文献
9.
Identification and characterization of an essential telomeric repeat binding factor in fission yeast 总被引:1,自引:0,他引:1
Whereas mammalian cells harbor two double strand telomeric repeat binding factors, TRF1 and TRF2, the fission yeast Schizosaccharomyces pombe has been thought to harbor solely the TRF1/TRF2 ortholog Taz1p to perform comparable functions. Here we report the identification of telomeric repeat binding factor 1 (Tbf1), a second TRF1/TRF2 ortholog in S. pombe. Like the Taz1p, the identified Tbf1p shares amino acid sequence similarity, as well as structural and functional characteristics, with the mammalian TRF1 and TRF2 proteins. This family of proteins shares a common architecture with two separate structural domains. An N-terminal domain is necessary and sufficient for the formation of homodimers, and a C-terminal MYB/homeodomain mediates sequence specific recognition of double-stranded telomeric DNA. The identified Tbf1p binds S. pombe telomeric DNA with high sequence specificity in vitro. Targeted deletion of the tbf1 gene reveals that it is essential for survival, and overexpression of the tbf1 gene leads to telomere elongation in vivo, which is dependent upon the MYB domain. These data suggest that fission yeast, like mammals, have two factors that bind double-stranded telomeric DNA and perform distinct roles in telomere length regulation. 相似文献
10.
The intermolecular interaction energies in central guanine triad of telomeric B-DNA were estimated based on ab initio quantum
chemistry calculations on the MP2/aDZ level of theory. The source of structural information was molecular dynamics simulation
of both canonical (AGGGTT) and oxidized (AG8oxoGGTT) telomere units. Our calculations demonstrate that significant stiffness
of central triad occurs if 8oxoG is present. The origin of such feature is mainly due to the increase of stacking interactions
of 8oxoG with neighbouring guanine molecules and stronger hydrogen bonding formation of 8oxoG with cytosine if compared with
canonical guanine. Another interesting observation is the context independence of stacking interactions of 8oxoG. Unlike to
5′-G2/G3-3′ and 5′-G3/G4-3′ sequences which are energetically different, 5′-G2/8oxoG3-3′ and 5′-8oxoG3/G4-3′ sequences are almost iso-energetic. 相似文献
11.
12.
Smogorzewska A van Steensel B Bianchi A Oelmann S Schaefer MR Schnapp G de Lange T 《Molecular and cellular biology》2000,20(5):1659-1668
Telomere length in human cells is controlled by a homeostasis mechanism that involves telomerase and the negative regulator of telomere length, TRF1 (TTAGGG repeat binding factor 1). Here we report that TRF2, a TRF1-related protein previously implicated in protection of chromosome ends, is a second negative regulator of telomere length. Overexpression of TRF2 results in the progressive shortening of telomere length, similar to the phenotype observed with TRF1. However, while induction of TRF1 could be maintained over more than 300 population doublings and resulted in stable, short telomeres, the expression of exogenous TRF2 was extinguished and the telomeres eventually regained their original length. Consistent with their role in measuring telomere length, indirect immunofluorescence indicated that both TRF1 and TRF2 bind to duplex telomeric DNA in vivo and are more abundant on telomeres with long TTAGGG repeat tracts. Neither TRF1 nor TRF2 affected the expression level of telomerase. Furthermore, the presence of TRF1 or TRF2 on a short linear telomerase substrate did not inhibit the enzymatic activity of telomerase in vitro. These findings are consistent with the recently proposed t loop model of telomere length homeostasis in which telomerase-dependent telomere elongation is blocked by sequestration of the 3' telomere terminus in TRF1- and TRF2-induced telomeric loops. 相似文献
13.
14.
Generation and characterization of telomere length maintenance in tankyrase 2-deficient mice
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Chiang YJ Nguyen ML Gurunathan S Kaminker P Tessarollo L Campisi J Hodes RJ 《Molecular and cellular biology》2006,26(6):2037-2043
Telomere length and function are crucial factors that determine the capacity for cell proliferation and survival, mediate cellular senescence, and play a role in malignant transformation in eukaryotic systems. The telomere length of a specific mammalian species is maintained within a given range by the action of telomerase and telomere-associated proteins. TRF1 is a telomere-associated protein that inhibits telomere elongation by its binding to telomere repeats, preventing access to telomerase. Human TRF1 interacts with tankyrase 1 and tankyrase 2 proteins, two related members of the tankyrase family shown to have poly(ADP-ribose) polymerase activity. Human tankyrase 1 is reported to ADP-ribosylate TRF1 and to down-regulate the telomeric repeat binding activity of TRF1, resulting in telomerase-dependent telomere elongation. Human tankyrase 2 is proposed to have activity similar to that of tankyrase 1, although tankyrase 2 function has been less extensively characterized. In the present study, we have assessed the in vivo function of mouse tankyrase 2 by germ line gene inactivation and show that inactivation of tankyrase 2 does not result in detectable alteration in telomere length when monitored through multiple generations of breeding. This finding suggests that either mouse tankyrases 1 and 2 have redundant functions in telomere length maintenance or that mouse tankyrase 2 differs from human tankyrase 2 in its role in telomere length maintenance. Tankyrase 2 deficiency did result in a significant decrease in body weight sustained through at least the first year of life, most marked in male mice, suggesting that tankyrase 2 functions in potentially telomerase-independent pathways to affect overall development and/or metabolism. 相似文献
15.
16.
Using a modified single telomere length analysis protocol (STELA) to clone and examine the sequence composition of individual human XpYp telomeres, we discovered a distinct class of extremely short telomeres in human cancer cells with active telomerase. We name them "t-stumps," to distinguish them from the well-regulated longer bulk telomeres. T-stumps contained arrangements of telomeric repeat variants and a minimal run of seven canonical telomeric TTAGGG repeats, but all could bind at least one TRF1 or TRF2 in vitro. The abundance of t-stumps was unaffected by ATM alteration but could be changed by manipulating telomerase catalytic subunit (hTERT) levels in cancer cells. We propose that in the setting of active telomerase and compromised checkpoints characteristic of human cancer cells, t-stumps define the minimal telomeric unit that can still be protected by a TRF1/TRF2-capping complex and, further, that hTERT (or telomerase) may have a role in protecting t-stumps. 相似文献
17.
Functional interaction between poly(ADP-Ribose) polymerase 2 (PARP-2) and TRF2: PARP activity negatively regulates TRF2 总被引:10,自引:0,他引:10
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Dantzer F Giraud-Panis MJ Jaco I Amé JC Schultz I Blasco M Koering CE Gilson E Ménissier-de Murcia J de Murcia G Schreiber V 《Molecular and cellular biology》2004,24(4):1595-1607
The DNA damage-dependent poly(ADP-ribose) polymerase-2 (PARP-2) is, together with PARP-1, an active player of the base excision repair process, thus defining its key role in genome surveillance and protection. Telomeres are specialized DNA-protein structures that protect chromosome ends from being recognized and processed as DNA strand breaks. In mammals, telomere protection depends on the T(2)AG(3) repeat binding protein TRF2, which has been shown to remodel telomeres into large duplex loops (t-loops). In this work we show that PARP-2 physically binds to TRF2 with high affinity. The association of both proteins requires the N-terminal domain of PARP-2 and the myb domain of TRF2. Both partners colocalize at promyelocytic leukemia bodies in immortalized telomerase-negative cells. In addition, our data show that PARP activity regulates the DNA binding activity of TRF2 via both a covalent heteromodification of the dimerization domain of TRF2 and a noncovalent binding of poly(ADP-ribose) to the myb domain of TRF2. PARP-2(-/-) primary cells show normal telomere length as well as normal telomerase activity compared to wild-type cells but display a spontaneously increased frequency of chromosome and chromatid breaks and of ends lacking detectable T(2)AG(3) repeats. Altogether, these results suggest a functional role of PARP-2 activity in the maintenance of telomere integrity. 相似文献
18.
The ends of linear chromosomes are capped by protein–DNA complexes termed telomeres. Telomere repeat binding factors 1 and 2 (TRF1 and TRF2) bind specifically to duplex telomeric DNA and are critical components of functional telomeres. Consequences of telomere dysfunction include genomic instability, cellular apoptosis or senescence and organismal aging. Mild oxidative stress induces increased erosion and loss of telomeric DNA in human fibroblasts. We performed binding assays to determine whether oxidative DNA damage in telomeric DNA alters the binding activity of TRF1 and TRF2 proteins. Here, we report that a single 8-oxo-guanine lesion in a defined telomeric substrate reduced the percentage of bound TRF1 and TRF2 proteins by at least 50%, compared with undamaged telomeric DNA. More dramatic effects on TRF1 and TRF2 binding were observed with multiple 8-oxo-guanine lesions in the tandem telomeric repeats. Binding was likewise disrupted when certain intermediates of base excision repair were present within the telomeric tract, namely abasic sites or single nucleotide gaps. These studies indicate that oxidative DNA damage may exert deleterious effects on telomeres by disrupting the association of telomere-maintenance proteins TRF1 and TRF2. 相似文献
19.
TRF1 and TRF2 are key components of vertebrate telomeres. They bind to double-stranded telomeric DNA as homodimers. Dimerization involves the TRF homology (TRFH) domain, which also mediates interactions with other telomeric proteins. The crystal structures of the dimerization domains from human TRF1 and TRF2 were determined at 2.9 and 2.2 A resolution, respectively. Despite a modest sequence identity, the two TRFH domains have the same entirely alpha-helical architecture, resembling a twisted horseshoe. The dimerization interfaces feature unique interactions that prevent heterodimerization. Mutational analysis of TRF1 corroborates the structural data and underscores the importance of the TRFH domain in dimerization, DNA binding, and telomere localization. A possible structural homology between the TRFH domain of fission yeast telomeric protein Taz1 with those of the vertebrate TRFs is suggested. 相似文献
20.
Anna K. Shchyolkina Lyudmila E. Minchenkova Elvira E. Minyat Yelena B. Khomyakova Valery I. Ivanov Reinhard Klement 《Journal of biomolecular structure & dynamics》2013,31(5):823-839
Abstract The formation of Antiparallel-Parallel-Combination (APC) DNA, a liner duplex with a segment of parallel-stranded (ps) helix flanked by conventional B-DNA, was tested with a number of synthetic oligonucleotides. The groove-binding ligand distamycin A (DstA) was used to stabilize the ps segment comprising five A·T base pairs. Two drug molecules bound per APC, one in each of the two equivalent grooves characteristic of ps-DNA. APC-DNA, reference molecules and their complexes with DstA were analysed by several methods: circular dichroism and absorption spectroscopy, thermal denaturation, chemical modification, and molecular modeling. The dye binding stoichiometry differed significantly due to inherent structural differences in the groove geometries of ps-DNA (trans base pairs, similar grooves) and conventional antiparallel-stranded (aps) B-DNA (cis base pairs, distinct major and minor grooves). The data support the existence of APC folding in solution. 相似文献