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Abstract

The physiological and pharmacological role of nucleic acids structures folded into the non canonical G-quadruplex conformation have recently emerged. Their activities are targeted at vital cellular processes including telomere maintenance, regulation of transcription and processing of the pre-messenger or telomeric RNA. In addition, severe conditions like cancer, fragile X syndrome, Bloom syndrome, Werner syndrome and Fanconi anemia J are related to genomic defects that involve G-quadruplex forming sequences. In this connection G-quadruplex recognition and processing by nucleic acid directed proteins and enzymes represents a key event to activate or deactivate physiological or pathological pathways. In this review we examine protein-G-quadruplex recognition in physiologically significant conditions and discuss how to possibly exploit the interactions' selectivity for targeted therapeutic intervention. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

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Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer.

Paula J. Bates, Damian Laber, Donald M Miller … (2009)

Certain guanine-rich (G-rich) DNA and RNA molecules can associate intermolecularly or intramolecularly to form four stranded or "quadruplex" structures, which have unusual biophysical and biological properties. Several synthetic G-rich quadruplex-forming oligodeoxynucleotides have recently been investigated as therapeutic agents for various human diseases. We refer to these biologically active G-rich oligonucleotides as aptamers because their activities arise from binding to protein targets via shape-specific recognition (analogous to antibody-antigen binding). As therapeutic agents, the G-rich aptamers may have some advantages over monoclonal antibodies and other oligonucleotide-based approaches. For example, quadruplex oligonucleotides are non-immunogenic, heat stable and they have increased resistance to serum nucleases and enhanced cellular uptake compared to unstructured sequences. In this review, we describe the characteristics and activities of G-rich oligonucleotides. We also give a personal perspective on the discovery and development of AS1411, an antiproliferative G-rich phosphodiester oligonucleotide that is currently being tested as an anticancer agent in Phase II clinical trials. This molecule functions as an aptamer to nucleolin, a multifunctional protein that is highly expressed by cancer cells, both intracellularly and on the cell surface. Thus, the serendipitous discovery of the G-rich oligonucleotides also led to the identification of nucleolin as a new molecular target for cancer therapy.

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G-quadruplex structures: in vivo evidence and function.

Hans Lipps, Daniela Rhodes (2009)

Although many biochemical and structural studies have demonstrated that DNA sequences containing runs of adjacent guanines spontaneously fold into G-quadruplex DNA structures in vitro, only recently has evidence started to accumulate for their presence and function in vivo. Genome-wide analyses have revealed that functional genomic regions from highly divergent organisms are enriched in DNA sequences with G-quadruplex-forming potential, suggesting that G-quadruplexes could provide a nucleic-acid-based mechanism for regulating telomere maintenance, as well as transcription, replication and translation. Here, we review recent studies aimed at uncovering the in vivo presence and function of G-quadruplexes in genomes and RNA, with a particular focus on telomeric G-quadruplexes and how their formation and resolution is regulated to permit telomere synthesis.

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TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres.

Zhong Deng, Julie Norseen, Andreas Wiedmer … (2009)

Telomere-repeat-encoding RNA (referred to as TERRA) has been identified as a potential component of yeast and mammalian telomeres. We show here that TERRA RNA interacts with several telomere-associated proteins, including telomere repeat factors 1 (TRF1) and 2 (TRF2), subunits of the origin recognition complex (ORC), heterochromatin protein 1 (HP1), histone H3 trimethyl K9 (H3 K9me3), and members of the DNA-damage-sensing pathway. siRNA depletion of TERRA caused an increase in telomere dysfunction-induced foci, aberrations in metaphase telomeres, and a loss of histone H3 K9me3 and ORC at telomere repeat DNA. Previous studies found that TRF2 amino-terminal GAR domain recruited ORC to telomeres. We now show that TERRA RNA can interact directly with the TRF2 GAR and ORC1 to form a stable ternary complex. We conclude that TERRA facilitates TRF2 interaction with ORC and plays a central role in telomere structural maintenance and heterochromatin formation.

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PubMed ID:: 21549174

DOI:: 10.1016/j.biochi.2011.04.018

ScienceOpen disciplines: Chemistry

Keywords: Antibodies,chemistry,metabolism,Aptamers, Nucleotide,Base Sequence,DNA Helicases,Drug Design,G-Quadruplexes,Heterogeneous-Nuclear Ribonucleoproteins,Molecular Sequence Data,Peptides,genetics,Promoter Regions, Genetic,Protein Biosynthesis,Proteins,RNA Helicases,RNA, Untranslated,Telomere,Telomere-Binding Proteins,Transcription, Genetic

The evolving world of protein-G-quadruplex recognition: a medicinal chemist's perspective.

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Journal of Circulating Biomarkers

Most cited references 152

Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer.

G-quadruplex structures: in vivo evidence and function.

TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres.

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