title: Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway.
abstract: The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers.
authors: Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York, United States of America.
authors: Courtney A
authors: CA
authors: Lovejoy
authors: Wendi
authors: W
authors: Li
authors: Steven
authors: S
authors: Reisenweber
authors: Supawat
authors: S
authors: Thongthip
authors: Joanne
authors: J
authors: Bruno
authors: Titia
authors: T
authors: de Lange
authors: Saurav
authors: S
authors: De
authors: John H J
authors: JH
authors: Petrini
authors: Patricia A
authors: PA
authors: Sung
authors: Maria
authors: M
authors: Jasin
authors: Joseph
authors: J
authors: Rosenbluh
authors: Yaara
authors: Y
authors: Zwang
authors: Barbara A
authors: BA
authors: Weir
authors: Charlie
authors: C
authors: Hatton
authors: Elena
authors: E
authors: Ivanova
authors: Laura
authors: L
authors: Macconaill
authors: Megan
authors: M
authors: Hanna
authors: William C
authors: WC
authors: Hahn
authors: Neal F
authors: NF
authors: Lue
authors: Roger R
authors: RR
authors: Reddel
authors: Yuchen
authors: Y
authors: Jiao
authors: Kenneth
authors: K
authors: Kinzler
authors: Bert
authors: B
authors: Vogelstein
authors: Nickolas
authors: N
authors: Papadopoulos
authors: Alan K
authors: AK
authors: Meeker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D056970:Co-Repressor Proteins; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D042822:Genomic Instability; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D059765:Homologous Recombination; D006801:Humans; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D059505:Telomere Homeostasis / Q000235:genetics*; D000075924:X-linked Nuclear Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D006657:Histones; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D019098:Telomerase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein