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Maintaining genetic stability through TP53 mediated checkpoint control
G M Wahl1, S P Linke, T G Paulson
1Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Abstract:
TP53 serves as a key relay for signals elicited by cellular stresses arising from diverse environmental or therapeutic insults. This relay then activates a cell cycle arrest or cell death program, depending on the stimulus and cell type. The absence of TP53 function disables the cell death or arrest programmes, thereby allowing the emergence of variants with various types of genomic alterations. The data discussed focus on two different types of signals that trigger the TP53 relay system. Firstly, TP53 arrests cell cycle progression in response to the types of DNA damage most commonly detected in cells undergoing tumour progression. Secondly, TP53 is activated by specific depletion of ribonucleotide pools, which prevent cells from entering S phase under conditions that could lead to chromosome breakage. The contribution of both responses limits the emergence of genetic variants. The DNA damage induced arrest appears to be triggered by as few as one double strand break in normal human fibroblasts. Analysis of the arrest kinetics after ionizing radiation shows that TP53 activates a prolonged arrest response in cells with irreparable DNA damage and that high efficiency cell elimination is achieved by a process that can be activated over multiple cell cycles. These data indicate that the primary function of the TP53 arrest/apoptosis pathway in response to double strand break is to eliminate damaged cells from the proliferating population, not to allow additional time for lesion repair. However, it remains possible that repair of other types of damage may benefit from TP53 mediated arrest. Analyses in model genetic systems indicate that the absence of TP53 function allows, but does not ensure, a high intrinsic rate of genetic variation and that instability is increased substantially when cells proceed through S phase under inappropriate growth conditions. This implies that inactivation of TP53 function in combination with other genetic alterations, such as oncogene activation, could accelerate genomic instability and tumour progression.
Insights
The TP53 protein halts cell cycle progression or triggers cell death in response to DNA damage or low nucleotide pools, preventing genomic alterations. Its absence accelerates tumor progression by enabling genetic instability.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Biology
Background:
- TP53 is a critical tumor suppressor protein that responds to cellular stress.
- TP53 activation leads to cell cycle arrest or apoptosis, preventing genomic instability.
- Loss of TP53 function is common in cancer and associated with increased genomic alterations.
Purpose of the Study:
- To investigate the signaling pathways that activate TP53.
- To understand the role of TP53 in preventing genomic instability.
- To elucidate the consequences of TP53 inactivation in tumor progression.
Main Methods:
- Analysis of TP53-mediated cell cycle arrest in response to DNA damage.
- Investigating TP53 activation by ribonucleotide pool depletion.
- Studying the impact of TP53 loss on genomic stability in model systems.
Main Results:
- TP53 arrests cell cycle in response to DNA double-strand breaks and ribonucleotide depletion, limiting genetic variation.
- TP53-mediated arrest following DNA damage primarily eliminates damaged cells rather than facilitating repair.
- Absence of TP53 allows, but does not guarantee, increased genetic variation, especially when combined with other genetic alterations.
Conclusions:
- TP53 plays a crucial role in maintaining genomic stability by preventing cell proliferation with damaged DNA.
- Inactivation of TP53 accelerates tumor progression by promoting genomic instability.
- Targeting TP53 pathways or understanding its role in genomic instability is critical for cancer therapy.