Targeted gene knockout mediated by triple helix forming oligonucleotides

Majumdar, Angshuman; Khorlin, Alexander; Dyatkina, Natalia; Liu, Feng; Powell, J.R.; Liu, Jilan; Fei, Zhizhong; Khripine, Yu.; Watanabe, Kenji; George, J; Glazer, Peter M.; Seidman, Michael M.

doi:10.1038/2530

Cited by 157 publications

(124 citation statements)

References 31 publications

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“…This finding expands our understanding of both the recognition of distorted DNA structures by NER, and the processing of triplexes by NER that may contribute to the triplex-induced mutagenesis reported by our group and others (27,30,34,35,(52)(53)(54)(55)(56)(57)(58). In addition, both in vitro and in vivo studies have revealed a role for XPA in the induction of recombination by triple helix formation (28,29).…”

Section: Dna Damage Recognitionmentioning

confidence: 69%

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions

Vásquez

Christensen

et al. 2002

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

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111

128

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Nucleotide excision repair (NER) plays a central role in maintaining genomic integrity by detecting and repairing a wide variety of DNA lesions. Xeroderma pigmentosum complementation group A protein (XPA) is an essential component of the repair machinery, and it is thought to be involved in the initial step as a DNA damage recognition and͞or confirmation factor. Human replication protein A (RPA) and XPA have been reported to interact to form a DNA damage recognition complex with greater specificity for damaged DNA than XPA alone. The mechanism by which these two proteins recognize such a wide array of structures resulting from different types of DNA damage is not known. One possibility is that they recognize a common feature of the lesions, such as distortions of the helical backbone. We have tested this idea by determining whether human XPA and RPA proteins can recognize the helical distortions induced by a DNA triple helix, a noncanonical DNA structure that has been shown to induce DNA repair, mutagenesis, and recombination. We measured binding of XPA and RPA, together or separately, to substrates containing triplexes with three, two, or no strands covalently linked by psoralen conjugation and photoaddition. We found that RPA alone recognizes all covalent triplex structures, but also forms multivalent nonspecific DNA aggregates at higher concentrations. XPA by itself does not recognize the substrates, but it binds them in the presence of RPA. Addition of XPA decreases the nonspecific DNA aggregate formation. These results support the hypothesis that the NER machinery is targeted to helical distortions and demonstrate that RPA can recognize damaged DNA even without XPA.triple helix ͉ nucleotide excision repair B ecause genome stability is critical for cell survival, extremely sensitive DNA repair mechanisms have evolved to protect the genome from both internal and external assaults. Defects in these repair mechanisms can lead to severe disorders such as xeroderma pigmentosum, ataxia telangiectasia, Fanconi anemia, and Bloom syndrome (reviewed in refs. 1-5). One of the major consequences of these defects is an enhanced predisposition to cancer. It has been reported that 80-90% of human cancers are the result of DNA damage (6).Many types of DNA damage, spontaneous and induced, develop from both endogenous and exogenous sources. Exogenous damages, both chemical and physical, arise from exposure to UV and ionizing radiation and from natural and synthetic chemicals. Cellular metabolic processes lead to internal sources of DNA damage; for example, it is estimated that loss of a purine base (depurination) occurs at a rate of nearly 20,000 events per cell per day (7).In humans, different types of DNA damage are thought to be repaired by one of several mechanisms, including nucleotide excision repair (NER; reviewed in refs. 8 and 9). NER removes covalent DNA lesions and is the only known mechanism for removing bulky DNA adducts in humans. The damaged base is removed by endonucleolytic cleavage of the phosphodiester bond...

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Section: Dna Damage Recognitionmentioning

confidence: 69%

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions

Vásquez

Christensen

et al. 2002

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

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111

128

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“…Inoue et al, have reported that 2'-O-methyloligoribonucleotide derivatives are not subject to cleavage by RNase H, and that a 2'-O-methylribonucleotide:RNA duplex is thermally more stable than an RNA:RNA duplex [76]. 2'-O-methylribose (2'-OMe) and 2'-O-aminoethylribose (2'-AE) modified oligonucleotides have been synthesized and successfully used to induce mutations in cells via the formation of DNA:DNA:RNA triple helices [77,78]. Interestingly, extensive modification of TFOs with 2'-OMe and 2'-AE residues leads to increased binding affinity in vitro, but reduced activity in vivo [79].…”

Section: Chemical Modifications Of Tfosmentioning

confidence: 99%

DNA triple helices: Biological consequences and therapeutic potential

Jain

Wang²,

Vásquez³

2008

Biochimie

262

199

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DNA structure is a critical element in determining its function. The DNA molecule is capable of adopting a variety of non-canonical structures, including three-stranded (i.e. triplex) structures, which will be the focus of this review. The ability to selectively modulate the activity of genes is a longstanding goal in molecular medicine. DNA triplex structures, either intermolecular triplexes formed by binding of an exogenously applied oligonucleotide to a target duplex sequence, or naturally occurring intramolecular triplexes (H-DNA) formed at endogenous mirror repeat sequences, present exploitable features that permit site-specific alteration of the genome. These structures can induce transcriptional repression and site-specific mutagenesis or recombination. Triplex-forming oligonucleotides (TFOs) can bind to duplex DNA in a sequence specific fashion with high affinity, and can be used to direct DNA-modifying agents to selected sequences. H-DNA plays important roles in vivo and is inherently mutagenic and recombinogenic, such that elements of the H-DNA structure may be pharmacologically exploitable. In this review we discuss the biological consequences and therapeutic potential of triple helical DNA structures. We anticipate that the information provided will stimulate further investigations aimed toward improving DNA triplexrelated gene targeting strategies for biotechnological and potential clinical applications.

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“…Moreover, the interaction of TnsC with triplex DNA motifs may uncover further information protein recognition of triple-helical nucleic acids, providing new evidence of their potential biological roles. Although many useful applications for triplex DNA have been found over recent years (27,(45)(46)(47), their biological role remains to be demonstrated. is illustrated.…”

Section: Discussionmentioning

confidence: 99%

Recognition of triple-helical DNA structures by transposon Tn7

Rao

Miller

Craig

2000

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

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We have found that the bacterial transposon Tn7 can recognize and preferentially insert adjacent to triple-helical nucleic acid structures. Both synthetic intermolecular triplexes, formed through the pairing of a short triplex-forming oligonucleotide on a plasmid DNA, and naturally occurring mirror repeat sequences known to form intramolecular triplexes or H-form DNA are preferential targets for Tn7 insertion in vitro. This target site selectivity depends upon the recognition of the triplex region by a Tn7-encoded ATP-using protein, TnsC, which controls Tn7 target site selection: the interaction of TnsC with the triplex region results in recruitment and activation of the Tn7 transposase. Recognition of a nucleic acid structural motif provides both new information into the factors that influence Tn7's target site selection and broadens its targeting capabilities.

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Targeted gene knockout mediated by triple helix forming oligonucleotides

Cited by 157 publications

References 31 publications

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions

DNA triple helices: Biological consequences and therapeutic potential

Recognition of triple-helical DNA structures by transposon Tn7

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