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Variant repeats are interspersed throughout the telomeres and recruit nuclear receptors in ALT cells
被引:110
作者:
Conomos, Dimitri
[1
,3
]
Stutz, Michael D.
[1
,3
]
Hills, Mark
[4
]
Neumann, Axel A.
[1
,3
]
Bryan, Tracy M.
[2
,3
]
Reddel, Roger R.
[1
,3
]
Pickett, Hilda A.
[1
,3
]
机构:
[1] Childrens Med Res Inst, Canc Res Unit, Westmead, NSW 2145, Australia
[2] Childrens Med Res Inst, Cell Biol Unit, Westmead, NSW 2145, Australia
[3] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia
[4] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada
基金:
英国医学研究理事会;
关键词:
DNA-DAMAGE RESPONSE;
MUTANT TELOMERASE;
MRE11/RAD50/NBS1;
COMPLEX;
HOMOLOGOUS RECOMBINATION;
ALTERNATIVE MECHANISM;
MAMMALIAN TELOMERES;
ALTERED TELOMERES;
HUMAN-CHROMOSOMES;
CANCER-CELLS;
MAINTENANCE;
D O I:
10.1083/jcb.201207189
中图分类号:
Q2 [细胞生物学];
学科分类号:
071009 ;
090102 ;
摘要:
Telomeres in cells that use the recombination-mediated alternative lengthening of telomeres (ALT) pathway elicit a DNA damage response that is partly independent of telomere length. We therefore investigated whether ALT telomeres contain structural abnormalities that contribute to ALT activity. Here we used next generation sequencing to analyze the DNA content of ALT telomeres. We discovered that variant repeats were interspersed throughout the telomeres of ALT cells. We found that the C-type (TCAGGG) variant repeat predominated and created a high-affinity binding site for the nuclear receptors COUP-TF2 and TR4. Nuclear receptors were directly recruited to telomeres and ALT-associated characteristics were induced after incorporation of the C-type variant repeat by a mutant telomerase. We propose that the presence of variant repeats throughout ALT telomeres results from recombination-mediated telomere replication and spreading of variant repeats from the proximal regions of the telomeres and that the consequent binding of nuclear receptors alters the architecture of telomeres to facilitate further recombination.
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页码:893 / 906
页数:14
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