An investigation of DNA mismatch repair capacity under normal culture conditions and under conditions of supra-physiological challenge in human CD4+T cell clones from donors of different ages

Annett, Kathryn; Duggan, Orla; Freeburn, Robin W.; Hyland, Paul; Pawelec, Graham; Barnett, Yvonne

doi:10.1016/j.exger.2005.09.001

Cited by 24 publications

(22 citation statements)

References 22 publications

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“…However, when challenged with acridine mutagen ICR-191 to induce supra-physiological levels of mismatches, deficiencies in MMR were found in most late passage TCCs. We conclude that MMR has an important role in the maintenance of the relative levels of genomic stability in lymphocytes (Annett et al 2005). These findings on TCC from donors of various ages including very old subjects are consistent with the results of studies examining microsatellite instability at five different loci interspersed in the genome (CD4, VWA31, Tpox, Fes/FPS and p53).…”

Section: Telomere Lengths Dna Damage Levels Mitochondrialsupporting

confidence: 84%

Ageing and Senescence in Immune Cells In Vitro and In Vivo

Pawelec

Barnett

2016

Cellular Ageing and Replicative Senescence

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Since the discovery of T cell growth factor, now known as interleukin 2 (IL 2), it has been possible to serially culture normal human T lymphocytes, something that cannot be done with other immune cells such as B cells or monocytes/macrophages. This chapter will focus on cloning efficiencies of T cells from younger or older subjects, their longevity in culture under different conditions and the progressive changes occurring over their in vitro lifespan.

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Section: Telomere Lengths Dna Damage Levels Mitochondrialsupporting

confidence: 84%

Ageing and Senescence in Immune Cells In Vitro and In Vivo

Pawelec

Barnett

2016

Cellular Ageing and Replicative Senescence

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“…Several studies suggest that the capacity for MMR as judged by MSI or mismatch levels is diminished as a function of ageing possibly due to the loss of key MMR proteins (see, e.g. Annett et al, 2005;Ben Yehuda et al, 2000;Krichevsky et al, 2004;Neri et al, 2005). Although we do not know whether correlations between ageing and loss of MMR reflect a direct role for MMR in preventing ageing or are indirect consequences of the ageing process, these studies raise intriguing possibilities.…”

Section: Mmr and Ageingmentioning

confidence: 90%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

388

359

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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“…This most likely affects T cell functionality and immunocompetence, which is well known to be modified by aging. 7 Evidence from an in vitro culture model of human T cell clones (TCC) exposed to repetitive antigenic challenge 5,8,9 indicated that MSI increased with increasing cumulative population doublings (CPD) and that this was associated with altered MMR gene expression at the mRNA level. 10 Acquisition of MSI was also related to TCC donor age.…”

Section: Introductionmentioning

confidence: 99%

Altered Expression of Mismatch Repair Proteins Associated with Acquisition of Microsatellite Instability in a Clonal Model of Human T Lymphocyte Aging

Neri¹,

Pawelec

Facchini

et al. 2008

Rejuvenation Research

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The DNA mismatch repair system, the main postreplicative correction pathway in eukaryotic cells, has been shown to be involved in the acquisition of genetic damage during the aging of normal somatic cells, including those of the immune system. Previously, we showed that some but not all human T cell clones (TCC) in an in vitro culture aging model develop microsatellite instability (MSI), which is associated with altered expression of mismatch repair genes. Here, we analyzed levels of mismatch repair proteins as well as the corresponding mRNAs and related this to the development of microsatellite instability in TCC. Msh2, Msh3, Msh6, Pms1, and Pms2 protein expression was quantified by Western blotting. We found that clones not manifesting microsatellite instability in this in vitro model of T cell replicative aging, induced by persistent antigenic stimulation, maintain normal transcriptional control and coordination among the mismatch repair system genes, while clones which do manifest MSI display a general deregulation of gene expression, which is likely to contribute to its occurrence.

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An investigation of DNA mismatch repair capacity under normal culture conditions and under conditions of supra-physiological challenge in human CD4+T cell clones from donors of different ages

Cited by 24 publications

References 22 publications

Ageing and Senescence in Immune Cells In Vitro and In Vivo

Ageing and Senescence in Immune Cells In Vitro and In Vivo

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Altered Expression of Mismatch Repair Proteins Associated with Acquisition of Microsatellite Instability in a Clonal Model of Human T Lymphocyte Aging

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