Back to Search
Start Over
Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.
- Source :
-
Science (New York, N.Y.) [Science] 2015 Jan 16; Vol. 347 (6219), pp. 273-7. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015, American Association for the Advancement of Science.)
- Subjects :
- Apoptosis
Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors
Ataxia Telangiectasia Mutated Proteins metabolism
Cell Cycle
Cell Line, Tumor
DNA Helicases genetics
DNA Helicases metabolism
Gene Knockdown Techniques
Glioma drug therapy
Glioma genetics
HeLa Cells
Homologous Recombination
Humans
Nuclear Proteins genetics
Nuclear Proteins metabolism
Osteosarcoma drug therapy
Osteosarcoma genetics
Promyelocytic Leukemia Protein
RNA, Untranslated genetics
RNA, Untranslated metabolism
Replication Protein A metabolism
Telomerase metabolism
Telomere genetics
Telomeric Repeat Binding Protein 2 metabolism
Transcription Factors metabolism
Tumor Suppressor Proteins metabolism
X-linked Nuclear Protein
Antineoplastic Agents pharmacology
Pyrazines pharmacology
Sulfones pharmacology
Telomere drug effects
Telomere metabolism
Telomere Homeostasis
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 347
- Issue :
- 6219
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 25593184
- Full Text :
- https://doi.org/10.1126/science.1257216