G-Quadruplex DNA Sequences Are Evolutionarily Conserved and Associated with Distinct Genomic Features in Saccharomyces cerevisiae

Capra, John A.; Paeschke, Katrin; Singh, Mona; Zakian, Virginia A.

doi:10.1371/journal.pcbi.1000861

Cited by 241 publications

(301 citation statements)

References 65 publications

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“…Promoter G4 sequences often contain five tracks of guanines, leading to swapping of the spare guanine track for the track containing the damaged guanine (47). Additionally, it is known that DNA double strand breaks occur more frequently at G4 sequences (62). During repair of dsDNA breaks, resection generates ssDNA regions in which quadruplexes can form when the appropriate sequences are present.…”

Section: Discussionmentioning

confidence: 99%

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

Byrd¹,

Zybailov

Maddukuri³

et al. 2016

Journal of Biological Chemistry

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Cells engage numerous signaling pathways in response to oxidative stress that together repair macromolecular damage or direct the cell toward apoptosis. As a result of DNA damage, mitochondrial DNA or nuclear DNA has been shown to enter the cytoplasm where it binds to "DNA sensors," which in turn initiate signaling cascades. Here we report data that support a novel signaling pathway in response to oxidative stress mediated by specific guanine-rich sequences that can fold into G-quadruplex DNA (G4DNA). In response to oxidative stress, we demonstrate that sequences capable of forming G4DNA appear at increasing levels in the cytoplasm and participate in assembly of stress granules. Identified proteins that bind to endogenous G4DNA in the cytoplasm are known to modulate mRNA translation and participate in stress granule formation. Consistent with these findings, stress granule formation is known to regulate mRNA translation during oxidative stress. We propose a signaling pathway whereby cells can rapidly respond to DNA damage caused by oxidative stress. Guanine-rich sequences that are excised from damaged genomic DNA are proposed to enter the cytoplasm where they can regulate translation through stress granule formation. This newly proposed role for G4DNA provides an additional molecular explanation for why such sequences are prevalent in the human genome.

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Section: Discussionmentioning

confidence: 99%

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

Byrd¹,

Zybailov

Maddukuri³

et al. 2016

Journal of Biological Chemistry

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“…Palindromic sequences greater than 16 bp were examined using data from Lisnic et al (2005), and sequences likely to form G4 quadruplex structures were obtained from Dataset S1 of Capra et al (2010). Hershman et al (2008) examined differential expression of genes by S. cerevisiae in response to N-methyl mesoporphyrin IX (NMM), a drug that stabilizes G4 quadruplexes in vitro.…”

Section: Associating Genomic Elements With Loh Transitions In Sub-culmentioning

confidence: 99%

Elevated Genome-Wide Instability in Yeast Mutants Lacking RNase H Activity

O’Connell¹,

Jinks-Robertson

Petes

2015

Genetics

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Two types of RNA:DNA associations can lead to genome instability: the formation of R-loops during transcription and the incorporation of ribonucleotide monophosphates (rNMPs) into DNA during replication. Both ribonuclease (RNase) H1 and RNase H2 degrade the RNA component of R-loops, whereas only RNase H2 can remove one or a few rNMPs from DNA. We performed highresolution mapping of mitotic recombination events throughout the yeast genome in diploid strains of Saccharomyces cerevisiae lacking RNase H1 (rnh1D), RNase H2 (rnh201D), or both RNase H1 and RNase H2 (rnh1D rnh201D). We found little effect on recombination in the rnh1D strain, but elevated recombination in both the rnh201D and the double-mutant strains; levels of recombination in the double mutant were 50% higher than in the rnh201 single-mutant strain. An rnh201D mutant that additionally contained a mutation that reduces rNMP incorporation by DNA polymerase e (pol2-M644L) had a level of instability similar to that observed in the presence of wild-type Pol e. This result suggests that the elevated recombination observed in the absence of only RNase H2 is primarily a consequence of R-loops rather than misincorporated rNMPs.KEYWORDS RNase H1; RNase H2; loss of heterozygosity; mitotic recombination; microarrays R NA transcripts can stably associate with the DNA template during transcription, giving rise to R-loop structures containing an RNA:DNA hybrid and an unpaired DNA strand. Such R-loops can stall DNA replication forks and are a major source of recombination events that are stimulated by high levels of transcription (reviewed by Aguilera and Garcia-Muse 2012). Transcription-associated recombination (TAR) is generally strongest when the transcription machinery and a replication fork approach each other head on (Prado and Aguilera 2005), but there is also an orientation-independent component to such conflicts ). Importantly, TAR is highly elevated when RNA processing is perturbed and R-loops accumulate, or when R-loop removal mechanisms are disabled. The RNA component of R-loops can be removed by the Sen1 RNA-DNA helicase (Mischo et al. 2011) or degraded by ribonuclease (RNase) H1 or RNase H2 (reviewed in Cerritelli and Crouch 2009), which are generally considered to be functionally redundant.R-loops in yeast have been quantified genome-wide using immunoprecipitation with an antibody specific to DNA:RNA hybrids, followed by hybridization to a microarray or by DNA sequencing. This type of analysis has been done in wild type (Chan et al. 2014;El Hage et al. 2014), mRNA processing defective (Chan et al. 2014), RNase H-defective (Chan et al. 2014;El Hage et al. 2014), and RNA-DNA helicase (Sen1)-defective strains (Chan et al. 2014). In wild-type strains, Chan et al. (2014) observed RNA-DNA hybrid accumulation at Ty retrotransposons, near telomeres, within the ribosomal RNA (rRNA) gene cluster, and at highly transcribed GC-rich genes. El Hage et al. (2014) found hybrid accumulation in wild-type strains at highly transcribed genes, within the rRNA gen...

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“…Most ligands can affect telomere stability, with the formation of chromosomal end fusions, anaphase bridges (Capra et al, 2010), and translocations resulting in mitotic catastrophe (Tauchi et al, 2003;Pennarun et al, 2005;Shimizu et al, 2005). Nevertheless, not only telomeric end-to-end fusions but also the reorganization of telomeres in three-dimensional (3D) interphase nuclei (e.g., the formation of so-called telomeric aggregates) can result in chromosomal instability (Chuang et al, 2004;Louis et al, 2005), an effect that possibly also plays a role in G-quadruplex effects on the genome.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the Antiproliferative Activity of Some Naphthalene Diimide G-Quadruplex Ligands

et al. 2012

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G-quadruplexes are higher-order nucleic acid structures that can form in G-rich telomeres and promoter regions of oncogenes. Telomeric quadruplex stabilization by small molecules can lead to telomere uncapping, followed by DNA damage response and senescence, as well as chromosomal fusions leading to deregulation of mitosis, followed by apoptosis and downregulation of oncogene expression. We report here on investigations into the mechanism of action of tetra-substituted naphthalene diimide ligands on the basis of cell biologic data together with a National Cancer Institute COMPARE study. We conclude that four principal mechanisms of action are implicated for these compounds: 1) telomere uncapping with subsequent DNA damage response and senescence; 2) inhibition of transcription/translation of oncogenes; 3) genomic instability through telomeric DNA end fusions, resulting in mitotic catastrophe and apoptosis; and 4) induction of chromosomal instability by telomere aggregate formation.

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G-Quadruplex DNA Sequences Are Evolutionarily Conserved and Associated with Distinct Genomic Features in Saccharomyces cerevisiae

Cited by 241 publications

References 65 publications

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

Elevated Genome-Wide Instability in Yeast Mutants Lacking RNase H Activity

Mechanism of the Antiproliferative Activity of Some Naphthalene Diimide G-Quadruplex Ligands

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