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Different telomere damage signaling pathways in human and mouse cells
Agata Smogorzewska1, Titia de Lange
1Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, NY 10021, USA.
Abstract:
Programmed telomere shortening in human somatic cells is thought to act as a tumor suppressor pathway, limiting the replicative potential of developing tumor cells. Critically short human telomeres induce senescence either by activating p53 or by inducing the p16/RB pathway, and suppression of both pathways is required to suppress senescence of aged human cells. Here we report that removal of TRF2 from human telomeres and the ensuing de-protection of chromosome ends induced immediate premature senescence. Although the telomeric tracts remained intact, the TRF2(DeltaBDeltaM)-induced premature senescence was indistinguishable from replicative senescence and could be mediated by either the p53 or the p16/RB pathway. Telomere de-protection also induced a growth arrest and senescent morphology in mouse cells. However, in this setting the loss of p53 function was sufficient to completely abrogate the arrest, indicating that the p16/RB response to telomere dysfunction is not active in mouse cells. These findings reveal a fundamental difference in telomere damage signaling in human and mouse cells that bears on the use of mouse models for the telomere tumor suppressor pathway.
Insights
Removing TRF2 protein from telomeres triggers premature cell aging (senescence) in human cells, similar to natural aging. Mouse cells show a different response, highlighting species differences in telomere signaling.
Area of Science:
- Cellular senescence
- Telomere biology
- Cancer research
Background:
- Programmed telomere shortening acts as a tumor suppressor mechanism by limiting cell replication.
- Critical telomere length induces senescence via p53 or p16/RB pathways in human cells.
- Both p53 and p16/RB pathways must be suppressed to overcome senescence in aged human cells.
Purpose of the Study:
- To investigate the consequences of TRF2 removal from human telomeres.
- To compare telomere dysfunction responses between human and mouse cells.
Main Methods:
- Removal of TRF2 (Telomere Repeat-Binding Factor 2) from human telomeres.
- Observation of induced premature senescence and cell cycle arrest.
- Analysis of p53 and p16/RB pathway involvement in human and mouse cells.
Main Results:
- TRF2 removal induced immediate premature senescence in human cells, mimicking replicative senescence.
- Human cell senescence was mediated by either the p53 or the p16/RB pathway.
- Mouse cells exhibited growth arrest and senescence upon telomere de-protection, but p53 loss fully abrogated this, indicating p16/RB is inactive in mouse telomere response.
Conclusions:
- Telomere de-protection via TRF2 removal triggers senescence through distinct pathways in human cells.
- A fundamental difference exists in telomere damage signaling between human and mouse cells.
- Findings impact the utility of mouse models for studying the telomere tumor suppressor pathway.