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p53 prevents entry into mitosis with uncapped telomeres
Maria Thanasoula1, Jose Miguel Escandell, Paula Martinez
1Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Old Road Campus, Oxford OX37DQ, UK.
Current Biology : CB
|March 16, 2010
Summary
The p53/p21 pathway monitors telomere capping after DNA replication. This surveillance delays cell cycle progression into mitosis if telomeres remain uncapped, preventing DNA damage.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Telomeres, the protective caps of chromosomes, are essential for genomic stability.
- Telomere uncapping triggers DNA damage responses, but the cell cycle regulation of this process is poorly understood.
- The G2/M transition is a critical checkpoint for DNA integrity before cell division.
Purpose of the Study:
- To investigate the role of cell-cycle surveillance in telomere capping.
- To determine if the p53/p21 pathway monitors telomere integrity at the G2/M transition.
- To elucidate the consequences of persistent telomere uncapping on cell cycle progression and genomic stability.
Main Methods:
- Analysis of human and mouse cells with and without p53 or p21.
- Monitoring telomere capping status and DNA damage foci (e.g., gammaH2AX) during the cell cycle.
- Induction of artificial telomere uncapping to assess its impact on mitotic entry.
Main Results:
- Cells lacking p53 or p21 prematurely enter mitosis with uncapped telomeres.
- Artificially uncapped telomeres delay mitotic entry in a p53- and p21-dependent manner.
- Persistent uncapped telomeres in p53-deficient cells are shorter and lead to end-to-end fusions.
Conclusions:
- A p53-dependent pathway surveils telomere capping post-replication.
- This pathway delays G2/M progression when telomeres are unprotected.
- This mechanism ensures proper telomere re-capping and prevents genomic instability during mitosis.
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