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

Abstract CX-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 g...

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Autores principales:	Tehmina Masud, Charles Soong, Hong Xu, Justina Biele, Saelin Bjornson, Steven McKinney, Samuel Aparicio
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0c06815b27ef4bb085b1d4ca77a4acee
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spelling	oai:doaj.org-article:0c06815b27ef4bb085b1d4ca77a4acee2021-12-02T14:49:43ZUbiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-546110.1038/s41598-021-88988-w2045-2322https://doaj.org/article/0c06815b27ef4bb085b1d4ca77a4acee2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88988-whttps://doaj.org/toc/2045-2322Abstract CX-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.Tehmina MasudCharles SoongHong XuJustina BieleSaelin BjornsonSteven McKinneySamuel AparicioNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-20 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tehmina Masud Charles Soong Hong Xu Justina Biele Saelin Bjornson Steven McKinney Samuel Aparicio Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461
description	Abstract CX-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.
format	article
author	Tehmina Masud Charles Soong Hong Xu Justina Biele Saelin Bjornson Steven McKinney Samuel Aparicio
author_facet	Tehmina Masud Charles Soong Hong Xu Justina Biele Saelin Bjornson Steven McKinney Samuel Aparicio
author_sort	Tehmina Masud
title	Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461
title_short	Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461
title_full	Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461
title_fullStr	Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461
title_full_unstemmed	Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461
title_sort	ubiquitin-mediated dna damage response is synthetic lethal with g-quadruplex stabilizer cx-5461
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0c06815b27ef4bb085b1d4ca77a4acee
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Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461

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