Probing the Telomere Damage Response.
Telomere dysfunctions, rendered through replicative attrition of telomeric DNA or due to the removal of shelterin components, are recognized as DNA double-stranded breaks (DSBs) by the DNA damage repair (DDR) pathway. This leads to the activation of DNA damage checkpoint sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, γ-H2AX and 53BP1, the ATM and ATR signal-transducing kinases, and downstream effectors, including Chk1, Chk2, and p53. Robust DNA damage response signals at dysfunctional telomeres, achieved by the complete deletion of TRF2 or by expressing dominant-negative mutant TPP1ΔRD, can be detected by their association with γ-H2AX and 53BP1 forming "telomere dysfunction induced foci (TIFs)." Induction of TIFs at telomeres provides an opportunity to quantify the extent of telomere dysfunction and monitor downstream signaling pathways.
Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar St., New Haven, CT, 06520, USA.
Rekha
R
Rai
Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar St., New Haven, CT, 06520, USA. s.chang@yale.edu.
Sandy
S
Chang
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D015398:Signal Transduction / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D004247:DNA; D064007:Ataxia Telangiectasia Mutated Proteins
DNA damage; Telomere dysfunction; Telomere-FISH; Telomere-induced foci