rDNA Chromatin Activity Status as a Biomarker of Sensitivity to the RNA Polymerase I Transcription Inhibitor CX-5461

Son, Jinbae; Hannan, Katherine M.; Poortinga, Gretchen; Hein, Nadine; Cameron, Donald P.; Ganley, Austen R. D.; Sheppard, Karen E.; Pearson, Richard B.; Hannan, Ross D.; Sanij, Elaine

doi:10.3389/fcell.2020.00568

Cited by 15 publications

(14 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with our results, active transcription of rDNA repeats has been found to enhance the sensitivity of cells to CX-5461 and DNA damage production (95). In cells, topological stresses induced by transcription are mainly resolved by the TOP1 protein (81).…”

Section: Transcription Drives Top2-dependent G4-ligand-induced Dsbssupporting

confidence: 91%

Transcription-associated topoisomerase 2α (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands

Bossaert

Pipier

Riou

et al. 2021

eLife

View full text Add to dashboard Cite

G-quadruplexes (G4) are non-canonical DNA structures found in the genome of most species including human. Small molecules stabilizing these structures, called G4 ligands, have been identified and, for some of them, shown to induce cytotoxic DNA double-strand breaks. Through the use of an unbiased genetic approach, we identify here topoisomerase 2-alpha (TOP2A) as a major effector of cytotoxicity induced by two clastogenic G4 ligands, pyridostatin and CX-5461, the latter molecule currently undergoing phase I/II clinical trials in oncology. We show that both TOP2 activity and transcription account for DNA break production following G4 ligand treatments. In contrast, clastogenic activity of these G4 ligands is countered by topoisomerase 1 (TOP1), which limits co-transcriptional G4 formation, and by factors promoting transcriptional elongation. Altogether our results support that clastogenic G4 ligands act as DNA structure-driven TOP2-poisons at transcribed regions bearing G4 structures.

show abstract

Section: Transcription Drives Top2-dependent G4-ligand-induced Dsbssupporting

confidence: 91%

Transcription-associated topoisomerase 2α (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands

Bossaert

Pipier

Riou

et al. 2021

eLife

View full text Add to dashboard Cite

show abstract

“…We have also shown that high rates of Pol I transcription and active rDNA chromatin status determine sensitivity to CX-5461 in OvCa cell lines . 9 MYC is a master regulator of Pol I transcription and we have shown that upregulation of Pol I transcription is required to drive malignant transformation in MYC-driven lymphoma. 10 Our data therefore suggest MYC-driven Pol I transcription and/or MYC-driven global transcription and replication stress underlie sensitivity to CX-5461.…”

Section: Cx-5461-induced Replication Stress Targets Fork Stability Inmentioning

confidence: 94%

CX-5461 can destabilize replication forks in PARP inhibitor-resistant models of ovarian cancer

Xuan

Pearson

Sanij

2020

Molecular & Cellular Oncology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The rationale for targeting ribosome biogenesis in cancer is based on experimental and clinical evidence showing that tumorigenesis is associated with quantitative increases in ribosome production and/or production of qualitatively-altered ribosome species [44,45,47,48,52,[170][171][172][173]. These characteristics have formed the basis for the development of new drugs that disrupt the activation of rRNA synthesis by directly targeting the formation and activity of the RNA pol I transcriptional complex on rDNA [51,[174][175][176]. Effective ribosome biogenesis inhibition in cancer cells has gained considerable attention with the development of the two inhibitors, CX-5461 and CX-3543, which selectively bind to rDNA-enriched G-quadruplex regions and halt ribosome production [51,175].…”

Section: Targeting Ribosome Rna Synthesis In Colorectal Cancermentioning

confidence: 99%

Ribosome Biogenesis Alterations in Colorectal Cancer

Slimane

Marcel

Fenouil

et al. 2020

Cells

View full text Add to dashboard Cite

Many studies have focused on understanding the regulation and functions of aberrant protein synthesis in colorectal cancer (CRC), leaving the ribosome, its main effector, relatively underappreciated in CRC. The production of functional ribosomes is initiated in the nucleolus, requires coordinated ribosomal RNA (rRNA) processing and ribosomal protein (RP) assembly, and is frequently hyperactivated to support the needs in protein synthesis essential to withstand unremitting cancer cell growth. This elevated ribosome production in cancer cells includes a strong alteration of ribosome biogenesis homeostasis that represents one of the hallmarks of cancer cells. None of the ribosome production steps escape this cancer-specific dysregulation. This review summarizes the early and late steps of ribosome biogenesis dysregulations described in CRC cell lines, intestinal organoids, CRC stem cells and mouse models, and their possible clinical implications. We highlight how this cancer-related ribosome biogenesis, both at quantitative and qualitative levels, can lead to the synthesis of ribosomes favoring the translation of mRNAs encoding hyperproliferative and survival factors. We also discuss whether cancer-related ribosome biogenesis is a mere consequence of cancer progression or is a causal factor in CRC, and how altered ribosome biogenesis pathways can represent effective targets to kill CRC cells. The association between exacerbated CRC cell growth and alteration of specific steps of ribosome biogenesis is highlighted as a key driver of tumorigenesis, providing promising perspectives for the implementation of predictive biomarkers and the development of new therapeutic drugs.

show abstract

rDNA Chromatin Activity Status as a Biomarker of Sensitivity to the RNA Polymerase I Transcription Inhibitor CX-5461

Cited by 15 publications

References 66 publications

Transcription-associated topoisomerase 2α (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands

Transcription-associated topoisomerase 2α (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands

CX-5461 can destabilize replication forks in PARP inhibitor-resistant models of ovarian cancer

Ribosome Biogenesis Alterations in Colorectal Cancer

Contact Info

Product

Resources

About