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Science. 2015 Jan 16;347(6219):273-7. doi: 10.1126/science.1257216.

Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Departments of Pharmacology & Experimental Therapeutics, and Medicine, Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA. zou.lee@mgh.harvard.edu rlflynn@bu.edu.
2
Departments of Pharmacology & Experimental Therapeutics, and Medicine, Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA.
3
Laboratoire de Radiopathologie, UMR 967, Institut de Radiobiologie Cellulaire et Moleculaire, CEA Fontenay-aux-Roses, France.
4
Deparment of Surgery and Brain Tumor Center, Massachusetts General Hospital, Boston, MA 02115, USA.
5
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Massachusetts General Hospital, Charlestown, MA 02129, USA.
6
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
7
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
8
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA. zou.lee@mgh.harvard.edu rlflynn@bu.edu.

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.

PMID:
25593184
PMCID:
PMC4358324
DOI:
10.1126/science.1257216
[Indexed for MEDLINE]
Free PMC Article

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