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1.
Cell Rep ; 14(5): 1032-1040, 2016 Feb 09.
Article in English | MEDLINE | ID: mdl-26832416

ABSTRACT

Cancer cells overcome replicative senescence by exploiting mechanisms of telomere elongation, a process often accomplished by reactivation of the enzyme telomerase. However, a subset of cancer cells lack telomerase activity and rely on the alternative lengthening of telomeres (ALT) pathway, a recombination-based mechanism of telomere elongation. Although the mechanisms regulating ALT are not fully defined, chronic replication stress at telomeres might prime these fragile regions for recombination. Here, we demonstrate that the replication stress response protein SMARCAL1 is a critical regulator of ALT activity. SMARCAL1 associates with ALT telomeres to resolve replication stress and ensure telomere stability. In the absence of SMARCAL1, persistently stalled replication forks at ALT telomeres deteriorate into DNA double-strand breaks promoting the formation of chromosome fusions. Our studies not only define a role for SMARCAL1 in ALT telomere maintenance, but also demonstrate that resolution of replication stress is a crucial step in the ALT mechanism.


Subject(s)
Cellular Senescence , DNA Helicases/metabolism , Stress, Physiological , Telomere Homeostasis , Telomere/metabolism , Cell Line, Tumor , Chromosome Aberrations , DNA Breaks, Double-Stranded , Humans , Rad51 Recombinase/metabolism
2.
Science ; 347(6219): 273-7, 2015 Jan 16.
Article in English | MEDLINE | ID: mdl-25593184

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.


Subject(s)
Antineoplastic Agents/pharmacology , Pyrazines/pharmacology , Sulfones/pharmacology , Telomere Homeostasis , Telomere/drug effects , Telomere/metabolism , 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
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