p53 governs telomere regulation feedback too, via TRF2.
p53 takes critical part in a number of positive and negative feedback loops to regulate carcinogenesis, aging and other biological processes. Uncapped or dysfunctional telomeres are an endogenous DNA damage that activates ATM kinase (ataxia telangiectasia mutated) and then p53 to induce cellular senescence or apoptosis. Our recent study shows that p53, a downstream effector of the telomere damage signaling, also functions upstream of the telomere‐capping protein complex by inhibiting one of its components, TRF2 (telomeric repeat binding factor 2). Since TRF2 inhibition leads to ATM activation, a novel positive feedback loop exists to amplify uncapped telomere‐induced, p53‐mediated cellular responses. Siah1 (seven in absentia homolog 1), a p53‐inducible E3 ubiquitin ligase, plays a key role in this feedback regulation by targeting TRF2 for ubiquitination and proteasomal degradation. Biological significance and therapeutic implications of this study are discussed.
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Izumi
I
Horikawa
Kaori
K
Fujita
Curtis C
CC
Harris
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000098563:Seven in Absentia Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019098:Telomerase
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