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Studying Age-dependent Genomic Instability using the S. cerevisiae Chronological Lifespan Model
Published on: September 29, 2011
Microsatellite instability in in vitro ageing of T lymphocyte clones
Simona Neri1, Luca Cattini, Andrea Facchini
1Laboratorio di Immunologia e Genetica, Istituto di Ricerca Codivilla Putti, IOR, Via di Barbiano 1/10, 40136 Bologna, Italy.
Abstract:
Repair of mismatches in mammalian cell DNA is mediated by a complex of proteins that constitute the so-called mismatch repair system (MMR), the main post-replicative pathway for the correction of replication errors. Loss of MMR (as exemplified by germline mutations in some MMR genes, leading to hereditary non-polyposis colorectal cancer) results in increased mutation rates at both coding sequences and in non-coding regions such as microsatellites. In order to evaluate possible functional alterations of this repair system during ageing that could affect immune system efficiency, we studied microsatellite instability at five different loci interspersed in the genome (CD4, VWA31, Tpox, Fes/FPS and p53) in total DNA from T lymphocyte clones derived from hematopoietic stem cells, or peripheral T cells of young or elderly subjects. In addition, these clones had been maintained for different periods in vitro to represent a culture model of ageing. We observed increasing instability accumulating with increasing passages in culture, particularly in CD34+cell-derived clones, but no clear donor age relationship.
Insights
DNA mismatch repair (MMR) corrects replication errors. This study found microsatellite instability increases with cell culture passage, suggesting an aging effect on DNA repair, but not directly linked to donor age.
Area of Science:
- Molecular Biology
- Genetics
- Immunology
Background:
- The mismatch repair (MMR) system corrects DNA replication errors in mammalian cells.
- Defects in MMR are linked to increased mutation rates and diseases like hereditary non-polyposis colorectal cancer.
- Age-related decline in immune function may involve alterations in DNA repair mechanisms.
Purpose of the Study:
- To investigate potential functional alterations in the MMR system during cellular aging.
- To assess the impact of aging on DNA repair efficiency and its relation to immune system function.
- To model cellular aging using T lymphocyte clones cultured in vitro.
Main Methods:
- Analysis of microsatellite instability at five genomic loci (CD4, VWA31, Tpox, Fes/FPS, p53).
- Study of T lymphocyte clones derived from hematopoietic stem cells and peripheral T cells.
- Comparison between clones from young and elderly subjects, and clones cultured for varying periods in vitro.
Main Results:
- Microsatellite instability increased with the number of passages in cell culture, indicating accumulation of errors over time.
- This effect was particularly pronounced in clones derived from CD34+ cells.
- No significant correlation was found between microsatellite instability and the chronological age of the DNA donor.
Conclusions:
- In vitro culture and prolonged passage induce genomic instability, mimicking aspects of cellular aging.
- The MMR system's efficiency may be compromised during cellular aging, independent of donor age.
- Further research is needed to fully understand the implications for immune system efficiency in aging individuals.
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