The Effect of Molecular Crowding on the Stability of Human  c-MYC Promoter Sequence I-Motif at Neutral pH

Cui, Jingjing; Waltman, Phillip; Le, Vu; Lewis, Edwin A.

doi:10.3390/molecules181012751

Cited by 107 publications

(135 citation statements)

References 58 publications

(67 reference statements)

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“…S9A). Because the higher molecular weight of PEG shows more stabilization of i-motif due to the excluded volume effect (23,24), the replication might not be effectively stalled by the addition of 20 wt% PEG200. In fact, the addition of 20 wt% PEG200 did not increase thermal stability of the (C 3 TA 2 ) 4 i-motif, whose T m was 28.7°C and −ΔG°3 7 was −1.4 kcal·mol −1 (SI Appendix, Table S2).…”

Section: Dependence Of Replication Efficiency On I-motif Stabilitymentioning

confidence: 99%

“…S9E). Although the detailed mechanism of stabilization of the i-motif structure by PEG1000 is unknown, the higher molecular-weight PEG shifts the pK a of N3 in the cytosine base (23,24). As the i-motif structure is very compact compared with a random coil, a more pronounced excluded volume effect of higher molecular-weight PEG1000 compared with that of PEG200 may contribute to the observed effect of PEG1000 on the replication of an i-motif-forming DNA.…”

Section: Dependence Of Replication Efficiency On I-motif Stabilitymentioning

confidence: 99%

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Topological impact of noncanonical DNA structures on Klenow fragment of DNA polymerase

Takahashi

Brazier

Sugimoto

2017

Proc. Natl. Acad. Sci. U.S.A.

113

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Noncanonical DNA structures that stall DNA replication can cause errors in genomic DNA. Here, we investigated how the noncanonical structures formed by sequences in genes associated with a number of diseases impacted DNA polymerization by the Klenow fragment of DNA polymerase. Replication of a DNA sequence forming an i-motif from a telomere, hypoxia-induced transcription factor, and an insulin-linked polymorphic region was effectively inhibited. On the other hand, replication of a mixed-type G-quadruplex (G4) from a telomere was less inhibited than that of the antiparallel type or parallel type. Interestingly, the i-motif was a better inhibitor of replication than were mixed-type G4s or hairpin structures, even though all had similar thermodynamic stabilities. These results indicate that both the stability and topology of structures formed in DNA templates impact the processivity of a DNA polymerase. This suggests that i-motif formation may trigger genomic instability by stalling the replication of DNA, causing intractable diseases.oncanonical intramolecular structures of nucleic acids, such as a triplex and a quadruplex, are stabilized under conditions that mimic the crowded cellular conditions (1), and have been detected in cells (2, 3). In vitro and in vivo, guaninequadruplex (G-quadruplex or G4) formation inhibits transcription and translation of template nucleic acids (4-8). It is possible that the noncanonical structures act as "functional codes" triggered by different molecular environments, which regulate gene expression epigenetically (6, 7). As sequences capable of forming the noncanonical structures are found in telomeres and promoter regions of known oncogenes, alterations of the noncanonical structures could play important roles in the progression of cancer and in other diseases (9).One of the remarkable features of noncanonical structures of nucleic acids is the diversity of topologies. In the case of G4s, antiparallel, mixed, and parallel type structures have been characterized ( Fig. 1 A-C). The sequences complementary to regions capable of G4 formation are composed of tandem repeats of cytosine, and these C-rich regions can form a different type of tetraplex topology, which is the i-motif (10, 11). An intramolecular i-motif is formed upon the interaction of four C-rich regions. The structure has three loops and two parallel-stranded hairpin-like units stabilized by cytosine and protonated cytosine (C:C + ) base pairs that are vertically intercalated antiparallel to one another ( Fig. 1 D and E). The i-motif structures are categorized into class I and class II based on the lengths of the loops. C-rich sequences are found in telomeres and in the promoter regions of about 40% of human genes (12, 13). As the i-motif is stabilized by hydrogen bonding in C:C + base pairs (14, 15), acidic conditions stabilize the structure. As the i-motif can mediate transcriptional regulation of B-cell lymphoma 2 (Bcl2) oncogene in cells (16), the environment inside these cells might be favorable to i-motif formation....

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Section: Dependence Of Replication Efficiency On I-motif Stabilitymentioning

confidence: 99%

Section: Dependence Of Replication Efficiency On I-motif Stabilitymentioning

confidence: 99%

Topological impact of noncanonical DNA structures on Klenow fragment of DNA polymerase

Takahashi

Brazier

Sugimoto

2017

Proc. Natl. Acad. Sci. U.S.A.

113

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“…[16] i-Motifs can also exist at neutralp Hu nder molecular crowded conditions [17] and under transcriptionally induced negative superhelicity. [18] The recent remarkable finding that the transcription of centromeric alpha-satellite DNA during mitosis is required for centromere function [19] supports the conclusion that negative superhelicity conditions may be commoni nt hese regions and, consequently,f avor i-motif formation under physiological conditions.…”

Section: Introductionmentioning

confidence: 99%

Centromeric Alpha‐Satellite DNA Adopts Dimeric i‐Motif Structures Capped by AT Hoogsteen Base Pairs

Garavís

Escaja

Gabelica

et al. 2015

Chemistry A European J

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International audience© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Human centromeric alpha-satellite DNA is composed of tandem arrays of two types of 171 bp monomers; type A and type B. The differences between these types are concentrated in a 17 bp region of the monomer called the A/B box. Here, we have determined the solution structure of the C-rich strand of the two main variants of the human alpha-satellite A box. We show that, under acidic conditions, the C-rich strands of two A boxes self-recognize and form a head-to-tail dimeric i-motif stabilized by four intercalated hemi-protonated C:C + base pairs. Interestingly, the stack of C:C + base pairs is capped by T:T and Hoogsteen A:T base pairs. The two main variants of the A box adopt a similar three-dimensional structure, although the residues involved in the formation of the i-motif core are different in each case. Together with previous studies showing that the B box (known as the CENP-B box) also forms dimeric i-motif structures, our finding of this non-canonical structure in the A box shows that centromeric alpha satellites in all human chromosomes are able to form i-motifs, which consequently raises the possibility that these structures may play a role in the structural organization of the centromere. Nucleosome organization: All human centromeric alpha-satellites contain sequences that can form dimeric i-motif structures in vitro (see figure). These regions occur every 171 bp and are found at the entrance and exit of the nucleosome. This finding suggests that the i-motif may play a role in the higher order nucleosome organization at the centromere. ; Peer Reviewe

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“…15 Nevertheless, only a few studies reported the i-motif folding at neutral pH. [16][17][18] In this study, we http://dx.…”

Section: Introductionmentioning

confidence: 90%

Stabilization of the i-motif structure by the intra-strand cross-link formation

Kikuta

Piao

Brazier

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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The Effect of Molecular Crowding on the Stability of Human c-MYC Promoter Sequence I-Motif at Neutral pH

Cited by 107 publications

References 58 publications

Topological impact of noncanonical DNA structures on Klenow fragment of DNA polymerase

Topological impact of noncanonical DNA structures on Klenow fragment of DNA polymerase

Centromeric Alpha‐Satellite DNA Adopts Dimeric i‐Motif Structures Capped by AT Hoogsteen Base Pairs

Stabilization of the i-motif structure by the intra-strand cross-link formation

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