Spontaneous occurrence of telomeric DNA damage response in the absence of chromosome fusions.
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.
Cesare
Anthony J
AJ
Cancer Research Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia.
Kaul
Zeenia
Z
Cohen
Scott B
SB
Napier
Christine E
CE
Pickett
Hilda A
HA
Neumann
Axel A
AA
Reddel
Roger R
RR
D002460:Cell Line; D002877:Chromosomes, Human / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D008954:Models, Biological; D045522:Recombinases / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism
D045522:Recombinases; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D019098:Telomerase