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Induction of a p95/Nbs1-mediated S phase checkpoint by telomere 3' overhang specific DNA
Mark S Eller1, Guang-Zhi Li, Reza Firoozabadi
1Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118-2394, USA.
Abstract:
Telomere shortening induces a nonproliferative senescent phenotype, believed to reduce cancer risk, and telomeres are involved in a poorly understood manner in responses to DNA damage. Although telomere disruption induces p53 and triggers apoptosis or cell cycle arrest, the features of the disrupted telomere that trigger this response and the precise mechanism involved are poorly understood. Using human cells, we show that DNA oligonucleotides homologous to the telomere 3' overhang sequence specifically induce and activate p53 and activate an S phase checkpoint by modifying the Nijmegen breakage syndrome protein, known to mediate the S phase checkpoint after DNA damage. These responses are mediated, at least in part, by the ATM kinase and are not attributable to disruption of cellular telomeres. Based on these and earlier data, we propose that these oligonucleotides mimic a physiological signal, exposure of the telomere 3' overhang due to opening of the normal telomere loop structure, and hence evoke these protective antiproliferative responses in the absence of DNA damage or telomere disruption.
Insights
DNA oligonucleotides mimicking telomere 3' overhangs activate protective cell responses. This study reveals how exposed telomere overhangs trigger p53 and cell cycle arrest, crucial for cancer prevention.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Telomere shortening causes senescence, a state thought to limit cancer risk.
- Telomeres' role in DNA damage response is unclear, though telomere disruption activates p53 and cell cycle arrest.
- The specific triggers and mechanisms for telomere-mediated DNA damage responses remain poorly understood.
Purpose of the Study:
- To investigate how specific telomere features trigger p53 activation and cell cycle arrest.
- To elucidate the mechanism by which telomere overhangs induce cellular protective responses.
- To determine if these responses are linked to actual telomere disruption.
Main Methods:
- Utilized human cells and DNA oligonucleotides homologous to telomere 3' overhang sequences.
- Assessed the induction and activation of p53.
- Investigated the modification of the Nijmegen breakage syndrome protein and S phase checkpoint activation.
- Examined the role of ATM kinase in mediating these responses.
Main Results:
- DNA oligonucleotides mimicking the telomere 3' overhang specifically induced p53 activation.
- These oligonucleotides activated an S phase checkpoint by modifying the Nijmegen breakage syndrome protein.
- ATM kinase partially mediated these observed responses.
- The effects were not due to the disruption of cellular telomeres.
Conclusions:
- Exposed telomere 3' overhangs, potentially mimicking physiological signals, can trigger protective antiproliferative responses.
- These responses, including p53 activation and S phase arrest, occur independently of actual DNA damage or telomere disruption.
- The findings suggest a novel mechanism for sensing telomere integrity and initiating cellular safeguards.