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

التفاصيل البيبلوغرافية
العنوان: Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461
المؤلفون: Tehmina Masud, Charles Soong, Hong Xu, Justina Biele, Saelin Bjornson, Steven McKinney, Samuel Aparicio
المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-20 (2021)
بيانات النشر: Nature Portfolio, 2021.
سنة النشر: 2021
المجموعة: LCC:Medicine
LCC:Science
مصطلحات موضوعية: Medicine, Science
الوصف: 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.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2045-2322
Relation: https://doaj.org/toc/2045-2322
DOI: 10.1038/s41598-021-88988-w
URL الوصول: https://doaj.org/article/0c06815b27ef4bb085b1d4ca77a4acee
رقم الأكسشن: edsdoj.0c06815b27ef4bb085b1d4ca77a4acee
قاعدة البيانات: Directory of Open Access Journals
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