Cancer cells rely on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative mortality. ALT is mediated by recombination and is prevalent in a subset of human cancers, yet whether it can be exploited therapeutically remains unknown. Loss of the chromatin-remodeling protein ATRX associates with ALT in cancers. Here, we show that ATRX loss compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of replication protein A (RPA) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR, a critical regulator of recombination recruited by RPA, disrupts ALT and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers.

Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors

Bersani F.;
2015-01-01

Abstract

Cancer cells rely on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative mortality. ALT is mediated by recombination and is prevalent in a subset of human cancers, yet whether it can be exploited therapeutically remains unknown. Loss of the chromatin-remodeling protein ATRX associates with ALT in cancers. Here, we show that ATRX loss compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of replication protein A (RPA) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR, a critical regulator of recombination recruited by RPA, disrupts ALT and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers.
2015
347
6219
273
277
Antineoplastic Agents; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Cycle; Cell Line, Tumor; DNA Helicases; Gene Knockdown Techniques; Glioma; HeLa Cells; Homologous Recombination; Humans; Nuclear Proteins; Osteosarcoma; Promyelocytic Leukemia Protein; Pyrazines; RNA, Untranslated; Replication Protein A; Sulfones; Telomerase; Telomere; Telomeric Repeat Binding Protein 2; Transcription Factors; Tumor Suppressor Proteins; X-linked Nuclear Protein; Telomere Homeostasis
Flynn R.L.; Cox K.E.; Jeitany M.; Wakimoto H.; Bryll A.R.; Ganem N.J.; Bersani F.; Pineda J.R.; Suva M.L.; Benes C.H.; Haber D.A.; Boussin F.D.; Zou L.
File in questo prodotto:
File Dimensione Formato  
Science 2015.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 1.41 MB
Formato Adobe PDF
1.41 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
ATR ATRX ALT 6-27 LZ.docx

Accesso riservato

Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 150.55 kB
Formato Microsoft Word XML
150.55 kB Microsoft Word XML   Visualizza/Apri   Richiedi una copia
Science2015.pdf

Accesso aperto

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 540.81 kB
Formato Adobe PDF
540.81 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1794927
Citazioni
  • ???jsp.display-item.citation.pmc??? 222
  • Scopus 370
  • ???jsp.display-item.citation.isi??? 350
social impact