Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.( Science. 2015 Jan 16;347(6219):273-7.)

報告日期: 2015/03/27
報告時間: 16:00/16:50
報告學生: 林原禾(以英文報告)
講評老師: 洪良宜
附件下載: 下載[1478-1425858671-1.pdf] 

Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors

Rachel Litman Flynn,1,2* Kelli E. Cox,2† Maya Jeitany,3† Hiroaki Wakimoto,4

Alysia R. Bryll,2 Neil J. Ganem,2 Francesca Bersani,1,5 Jose R. Pineda,3 Mario L. Suvà,1,6 Cyril H. Benes,1 Daniel A. Haber,1,5 Francois D. Boussin,3 Lee Zou1,6*

Science. 2015 Jan 16;347(6219):273-7. 

Speaker: Yuan-Ho Lin                                Date: 2015.3.27

Commentator: Liang-Yi Hung                    Place: Room 602

Abstract

  About 85% of human cancers this through upregulation of telomerase activity to elongate telomeres, but in 10–15% of human tumors in culture maintain their telomeres by a telomerase independent mechanism termed Alternative Lengthening of Telomeres (ALT). ALT cell is dependent on homologous recombination than telomerase positive cancer cells, therefore HR become an important target for cancer therapy. Recent studies have revealed that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines. In this paper they found that loss of ATRX, a chromatin-remodeling protein will cause cell-cycle regulation of the telomeric noncoding RNA TERRA be affected and maintain replication protein A (RPA) bound with telomeres after DNA replication. Moreover, the ALT positive cells were treated with ATR (a protein kinase) inhibitor or siRNA for ATR enable chromosome fragmentation and apoptosis in ALT cells. The data show that cancers reliant on recombination are hypersensitive to ATR inhibitors, offering an direction for future preclinical and clinical studies.

References

  1. Henson JD1, Reddel RR. Assaying and investigating Alternative Lengthening of Telomeres activity in human cells and cancers. FEBS Lett. 2010 Sep 10; 584(17):3800-11.
  2. Cesare AJ1, Reddel RR. Alternative lengthening of telomeres: models, mechanisms and implications.Nat Rev Genet. 2010 May; 11(5):319-30.