Journal Article

Spontaneous occurrence of telomeric DNA damage response in the absence of chromosome fusions

Pickett, Hilda A, Reddel, Roger R, Cesare, Anthony J, Cohen, Scott B, Napier, Christine E, Neumann, Axel A, Kaul, Zeenia

2009

Overview

Telomeric DNA is protected by the shelterin complex, whose disruption triggers DNA-damage responses, checkpoint activation and chromosomal fusions. Now analysis of human cell lines reveals a spontaneously occurring intermediate state in which the DNA-damage response is activated at the telomeres without cell cycle arrest or chromosomal fusions, and with TRF2 playing a central role in determining such a state. Telomere dysfunction is typically studied under conditions in which a component of the six-subunit shelterin complex that protects chromosome ends is disrupted. The nature of spontaneous telomere dysfunction is less well understood. Here we report that immortalized human cell lines lacking wild-type p53 function spontaneously show many telomeres with a DNA damage response (DDR), commonly affecting only one sister chromatid and not associated with increased chromosome end-joining. DDR + telomeres represent an intermediate configuration between the fully capped and uncapped (fusogenic) states. In telomerase activity–positive (TA + ) cells, DDR is associated with low TA and short telomeres. In cells using the alternative lengthening of telomeres mechanism (ALT + ), DDR is partly independent of telomere length, mostly affects leading strand–replicated telomeres, and can be partly suppressed by TRF2 overexpression. In ALT + (but not TA + ) cells, DDR + telomeres preferentially associate with large foci of extrachromosomal telomeric DNA and recombination proteins. DDR + telomeres therefore arise through different mechanisms in TA + and ALT + cells and have different consequences.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Biochemistry / Biological Microscopy / Biomedical and Life Sciences / Cell Line / Cellular biology / Chromosomal proteins / Chromosome abnormalities / Chromosomes / Chromosomes, Human - metabolism / Complications and side effects / Deoxyribonucleic acid / DNA / DNA Damage / Health aspects / Humans / Life Sciences / Membrane Biology / Models, Biological / Molecular biology / Molecular structure / Physiological aspects / Protein Structure / Recombinases - metabolism / Telomerase - metabolism / Telomere - metabolism / Telomeres / Telomeric Repeat Binding Protein 2 - metabolism