Altered expression of mismatch repair proteins associated with acquisition of microsatellite instability in a clonal model of human T lymphocyte aging.
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.
Neri
Simona
S
Laboratorio di Immunologia e Genetica, Istituto di Ricerca Codivilla-Putti, IOR, Bologna, Italy.
Pawelec
Graham
G
Facchini
Andrea
A
Ferrari
Cinzia
C
Mariani
Erminia
E
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000032:analysis / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016922:Cellular Senescence; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein / Q000032:analysis / Q000235:genetics; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes