DNA Damage Foci at Dysfunctional Telomeres

摘要: Abstract We report cytologic and genetic data indicating that telomere dysfunction induces a DNA damage response in mammalian cells. Dysfunctional, uncapped telomeres, created through inhibition of TRF2, became associated with factors, such as 53BP1, γ-H2AX, Rad17, ATM, Mre11. refer to the domain telomere-associated factors Telomere Dysfunction-Induced Focus (TIF). The accumulation 53BP1 on telomeres was reduced presence PI3 kinase inhibitors caffeine wortmannin, which affect ATR, DNA-PK. By contrast, Mre11 TIFs were resistant caffeine, consistent previous findings ionizing radiation. A-T cells had diminished TIF response, ATM is major transducer this pathway. However, absence TRF2 still induced senescence, pointing second ATM-independent conclude cellular governed by proteins also control response. represent new tool for evaluating status normal malignant suspected harboring dysfunctional telomeres. Furthermore, induction provides an opportunity study within context well-defined, physically marked lesions.