Abundance and degree of dispersion of genomic d(GA) n ·d(TC) n sequences

Manor, Haim; Rao, B. Sanjiva; Martin, Robert G.

doi:10.1007/bf02138367

Cited by 118 publications

(85 citation statements)

References 22 publications

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“…There is evidence that such sequences can form triplex DNA and non-B DNA structures and may cause pausing or arrest of DNA synthesis (5). Also, their distribution is statistically nonrandom and conserved in vertebrate chromosomes (54,79), also suggesting functional importance. Within this same region are three exact matches to the consensus sequence a PUR element from a yeast ARS plasmid abolished ARS identified by Bergemann and Johnson (9) as a binding site for activity (60), suggesting that this element may play a cona single-stranded DNA binding protein, designated PUR, served functional role in replication.…”

Section: Discussionmentioning

confidence: 99%

Analysis of a replication initiation sequence from the adenosine deaminase region of the mouse genome.

Virta-Pearlman¹,

Gunaratne²,

Chinault³

1993

Mol. Cell. Biol.

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A 4-kb HindII frgment that supported the efficient autonomous replication of plasmid vector pDY-, a replication-defective construct based on Epstein-Barr virus sequences, in human K562 cells was rescued from amplified double-minute chromosomes containing the murine adenosine deaminase locus. Polymerase chain reaction assays of size-fractionated nascent strands demonstrated that replication initiation occurred within the same 1-to 2-kb region of this fragment in autonomously replicating plasmids containing the sequence in either orientation, in double-minute chromosomes, and in the single-copy locus at its normal chromosomal location. The complete sequence of this fragment was determined; it contains a 248-bp polypurine tract and consensus binding site sequences for several putative transcription and replication factors.Our understanding of the molecular mechanisms of DNA replication in mammalian cells is largely based on the study of viruses. Although such studies have been extremely productive, there are certain aspects of chromosomal replication that cannot be addressed with such model systems. For example, although the initiation of viral replication is clearly dependent on specific sequences that are recognized by self-encoded proteins, such as simian virus 40 T antigen, neither the DNA signals nor the proteins involved in the initiation of replication in mammalian chromosomes have been defined. In addition, there are unique temporal and spatial controls that must come into play with chromosomal replication to coordinate the accurate and orderly duplication of each DNA base in the entire genome during the S phase.It is clear that for the replication of mammalian chromosomes during the S phase at the measured rates of replication fork movement, the initiation of DNA synthesis must occur at many sites. By analogy with prokaryotic systems (40, 44) and simple eukaryotic systems (10,11,24,42,43,51,80), one would expect this initiation to be dependent on specific signals. However, the continuing ambiguity about the identity of such signals must be due to one of two factors: either (i) they do not exist or (ii) the intrinsic complexity and/or redundancy of these signals make them difficult to dissect by standard approaches. The fact that many of the assays available to search for such sequences are both experimentally difficult and dependent on fundamental assumptions concerning the properties of putative replication intermediates further complicates this issue (74). The most promising candidates for mammalian chromosomal replication origins are sites flanking the DHFR locus in Chinese hamster cells (4, 12-15, 38, 53, 73, 75), and the c-myc locus in the human genome (55, 72), in which sequences have been implicated in origin activity by multiple assays. However, even at the most rigorously studied region 3' of the DHFR gene, the conclusions from different approaches have not been completely consistent; whereas some assays indicate sequence specificity in origin activity (14,37,73) (27,75). Models for the reconcilia...

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Section: Discussionmentioning

confidence: 99%

Analysis of a replication initiation sequence from the adenosine deaminase region of the mouse genome.

Virta-Pearlman¹,

Gunaratne²,

Chinault³

1993

Mol. Cell. Biol.

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“…1 They are involved in biological processes 2,3 such as DNA recombination, which is very likely a consequence of their peculiar structural properties. 3,4 They are known to form triplexes consisting of either two purine and one pyrimidine strands 5 in the presence of metal ions or two pyrimidine and one purine strands appearing at acidic pH.…”

Section: Introductionmentioning

confidence: 99%

Towards a better understanding of the unusual conformations of the alternating guanine–adenine repeat strands of DNA

et al. 2006

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Alternating guanine–adenine strands of DNA are known to self‐associate into a parallel‐stranded homoduplex at neutral pH, fold into an ordered single‐stranded structure at acid pH, and adopt yet another ordered single‐stranded conformer in aqueous ethanol. The unusual conformers melt cooperatively and exhibit distinct circular dichroism spectra suggestive of a substantial conformational order, but their molecular structures are not known yet. Here, we have probed the molecular structures using guanine and adenine analogs lacking the N7 atom, and thus unable of Hoogsteen pairing, or those restrained in the less‐frequent syn glycosidic orientation. The studies showed that the syn glycosidic orientation of dA residues promoted the neutral homoduplex, whereas the syn orientation of dG was incompatible with the homoduplex. In addition, Hoogsteen pairing of dA seemed to be a crucial property of the homoduplex whereas dG did not pair in this way. The situation was the same in both single‐stranded conformers with the dG residues. On the other hand, the presence of N7 was important with dA but its syn geometry was not favorable. The present data can be used as restraints to model the unusual molecular structures of the alternating guanine–adenine strands of DNA. © 2006 Wiley Periodicals, Inc. Biopolymers 85: 19–27, 2007.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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“…Patients with Werner syndrome (WS) 1 are characterized by premature aging (11) and a high incidence of certain cancers. They have elevated frequencies of spontaneous deletion mutations in the HPRT gene (12) and show a variety of karyotypic abnormalities including inversions, translocations, and chromosomal losses (13,14).…”

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confidence: 99%

Unwinding of a DNA Triple Helix by the Werner and Bloom Syndrome Helicases

Brosh¹,

Majumdar²,

Desai³

et al. 2001

Journal of Biological Chemistry

118

101

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Bloom syndrome and Werner syndrome are genome instability disorders, which result from mutations in two different genes encoding helicases. Both enzymes are members of the RecQ family of helicases, have a 3 3 5 polarity, and require a 3 single strand tail. In addition to their activity in unwinding duplex substrates, recent studies show that the two enzymes are able to unwind G2 and G4 tetraplexes, prompting speculation that failure to resolve these structures in Bloom syndrome and Werner syndrome cells may contribute to genome instability. The triple helix is another alternate DNA structure that can be formed by sequences that are widely distributed throughout the human genome. Here we show that purified Bloom and Werner helicases can unwind a DNA triple helix. The reactions are dependent on nucleoside triphosphate hydrolysis and require a free 3 tail attached to the third strand. The two enzymes unwound triplexes without requirement for a duplex extension that would form a fork at the junction of the tail and the triplex. In contrast, a duplex formed by the third strand and a complement to the triplex region was a poor substrate for both enzymes. However, the same duplex was readily unwound when a noncomplementary 5 tail was added to form a forked structure. It seems likely that structural features of the triplex mimic those of a fork and thus support efficient unwinding by the two helicases.Despite the obvious importance of genetic stability, the mammalian genome has an abundance of sequences that are potentially destabilizing. Elements that can form non-duplex structures, such as DNA triple helices (1, 2), G quartets (3-5), hairpins (6, 7), and cruciforms (8), all have the capacity to interfere with transcription and replication. Moreover, many studies have described the role of these elements in DNA rearrangements such as deletions, sister chromatid exchanges, homologous and illegitimate recombination events, etc. (reviewed in Refs. 9 and 10). With such an array of provocative sequence elements, it seems likely that cells would have developed the capacity for controlling the potential of these sequences for genome destabilization.Some insight into the nature of the enzymology involved in the maintenance of genetic integrity has come from the study of two "genome instability" disorders, Bloom and Werner syndrome. Patients with Werner syndrome (WS) 1 are characterized by premature aging (11) and a high incidence of certain cancers. They have elevated frequencies of spontaneous deletion mutations in the HPRT gene (12) and show a variety of karyotypic abnormalities including inversions, translocations, and chromosomal losses (13,14). The mutant gene in WS has been identified as a member of the RecQ helicase family, and the protein is a 3Ј-5Ј-helicase (15, 16) and a 3Ј-5Ј-exonuclease (17-19). A role in replication is implied by the demonstration that the WRN helicase interacts with and is stimulated by the human replication protein A (RPA) (20, 21). The protein has been recovered from cells in a replication comp...

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Abundance and degree of dispersion of genomic d(GA) n ·d(TC) n sequences

Cited by 118 publications

References 22 publications

Analysis of a replication initiation sequence from the adenosine deaminase region of the mouse genome.

Analysis of a replication initiation sequence from the adenosine deaminase region of the mouse genome.

Towards a better understanding of the unusual conformations of the alternating guanine–adenine repeat strands of DNA

Unwinding of a DNA Triple Helix by the Werner and Bloom Syndrome Helicases

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