The G-quadruplex ligand RHPS4 interferes with telomere replication leading to ATR-dependent DNA damage response

2008 ◽  
Vol 6 (9) ◽  
pp. 87-88
Author(s):  
A. Biroccio ◽  
A. Rizzo ◽  
E. Salvati ◽  
M. Stevens ◽  
M. Stevens ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
G Quadruplex ◽  
Damage Response ◽  
Telomere Replication

scholarly journals Dyads of G‐Quadruplex Ligands Triggering DNA Damage Response and Tumour Cell Growth Inhibition at Subnanomolar Concentration

2019 ◽  
Vol 25 (47) ◽  
pp. 11085-11097 ◽  
Author(s):  
Filippo Doria ◽  
Erica Salvati ◽  
Luca Pompili ◽  
Valentina Pirota ◽  
Carmen D'Angelo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Dna Damage Response ◽  
Tumour Cell ◽  
Cell Growth Inhibition ◽  
G Quadruplex ◽  
Damage Response ◽  
Tumour Cell Growth

scholarly journals TRF1 prevents permissive DNA damage response, recombination and Break Induced Replication at telomeres

2019 ◽  
Author(s):  
Rosa Maria Porreca ◽  
Pui Pik Law ◽  
Emilia Herrera-Moyano ◽  
Roser Gonzalez-Franco ◽  
Alex Montoya ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Dna Recombination ◽  
Protein Composition ◽  
Telomeric Dna ◽  
Chromatin Remodelers ◽  
Damage Response ◽  
Telomere Replication ◽  
Break Induced Replication ◽  
Chromatin Rearrangement

AbstractTelomeres are a significant challenge to DNA replication and are prone to replication stress and telomere fragility. The shelterin component TRF1 facilitates telomere replication but the molecular mechanism remains uncertain. By interrogating the proteomic composition of telomeres, we show that telomeres lacking TRF1 undergo protein composition reorganisation associated with a DNA damage response and chromatin remodelers. Surprisingly, TRF1 suppresses the accumulation of promyelocytic leukemia (PML) protein, BRCA1 and the SMC5/6 complex at telomeres, which is associated with increased Homologous Recombination (HR) and TERRA transcription. We uncovered a previously unappreciated role for TRF1 in the suppression of telomere recombination, dependent on SMC5 and also POLD3 dependent Break Induced Replication at telomeres. We propose that TRF1 facilitates S-phase telomeric DNA synthesis to prevent illegitimate mitotic DNA recombination and chromatin rearrangement.

scholarly journals Interrogating accessibility of telomeric sequences with FRET-PAINT: evidence for length-dependent telomere compaction

2021 ◽  
Author(s):  
Golam Mustafa ◽  
Sajad Shiekh ◽  
Keshav GC ◽  
Sanjaya Abeysirigunawardena ◽  
Hamza Balci
Keyword(s):  
Dna Damage ◽  
Telomere Length ◽  
Dna Damage Response ◽  
Single Molecule ◽  
Telomeric Repeat ◽  
Dna Molecules ◽  
Telomeric Dna ◽  
Telomeric Sequences ◽  
G Quadruplex ◽  
Damage Response

Abstract Single-stranded telomeric overhangs are ∼200 nucleotides long and can form tandem G-quadruplex (GQ) structures, which reduce their accessibility to nucleases and proteins that activate DNA damage response. Whether these tandem GQs further stack to form compact superstructures, which may provide better protection for longer telomeres, is not known. We report single-molecule measurements where the accessibility of 24–144 nucleotide long human telomeric DNA molecules is interrogated by a short PNA molecule that is complementary to a single GGGTTA repeat, as implemented in the FRET-PAINT method. Binding of the PNA strand to available GGGTTA sequences results in discrete FRET bursts which were analyzed in terms of their dwell times, binding frequencies, and topographic distributions. The binding frequencies were greater for binding to intermediate regions of telomeric DNA compared to 3′- or 5′-ends, suggesting these regions are more accessible. Significantly, the binding frequency per telomeric repeat monotonically decreased with increasing telomere length. These results are consistent with telomeres forming more compact structures at longer lengths, reducing accessibility of these critical genomic sites.

scholarly journals Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tehmina Masud ◽  
Charles Soong ◽  
Hong Xu ◽  
Justina Biele ◽  
Saelin Bjornson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Synthetic Lethality ◽  
Clinical Activity ◽  
Helicase Domain ◽  
Loss Of Function ◽  
Genome Maintenance ◽  
Synthetic Lethal ◽  
G Quadruplex ◽  
Damage Response

AbstractCX-5461 is a G-quadruplex (G4) ligand currently in trials with initial indications of clinical activity in cancers with defects in homologous recombination repair. To identify more genetic defects that could sensitize tumors to CX-5461, we tested synthetic lethality for 480 DNA repair and genome maintenance genes to CX-5461, pyridostatin (PDS), a structurally unrelated G4-specific stabilizer, and BMH-21, which binds GC-rich DNA but not G4 structures. We identified multiple members of HRD, Fanconi Anemia pathways, and POLQ, a polymerase with a helicase domain important for G4 structure resolution. Significant synthetic lethality was observed with UBE2N and RNF168, key members of the DNA damage response associated ubiquitin signaling pathway. Loss-of-function of RNF168 and UBE2N resulted in significantly lower cell survival in the presence of CX-5461 and PDS but not BMH-21. RNF168 recruitment and histone ubiquitination increased with CX-5461 treatment, and nuclear ubiquitination response frequently co-localized with G4 structures. Pharmacological inhibition of UBE2N acted synergistically with CX-5461. In conclusion, we have uncovered novel genetic vulnerabilities to CX-5461 with potential significance for patient selection in future clinical trials.

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