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Identifier

000366949

Title

Μεταβολές στη δομή και λειτουργία του κυτταρικού πυρήνα κατά τη διαδικασία της γήρανσης

Alternative Title

Structural and biochemical changes in the cell nucleus during in vitro senescence

Author

Χανδρής, Παναγιώτης

Thesis advisor

Κλέτσας, Δημήτρης

Reviewer

Θεοδωρόπουλος, Παναγιώτης
Γεωργάτος, Σπύρος
Στουρνάρας, Χρήστος
Γραβάνης, Αχιλλέας
Καρδάσης, Δημήτρης
Μαυροθαλασσίτης, Γιώργος

Abstract

The cellular aging (senescence) is a permanent arrest of cell proliferation despite the presence of external mitogens in the culture medium. Induced either by a gradual reduction in telomere length with subsequent genomic instability, or after effect of stress factors such as the presence of oncogenes or oxidative stress, cellular senescence is essentially a well-accepted system of reference for comparison in the investigation of cell signaling pathways as well as in the study of functional changes in subcellular organelle especially in pathological conditions. In this context the present study by using senescence of human diploid fibroblasts as a reference system, we have investigated structural and biochemical changes in the cell nucleus associated with lamins and enzymes that modify them in the carboxyterminus and more specifically the endoprotease Rce1 and the methyltransferase Icmt. Looking in more detail the role of these enzymes in cell cycle progression, the dissertation led to findings that suggest a regulatory role for the methyltransferase in the middle of G1 phase of the cell cycle, with the functioning of the enzyme being a prerequisite for entry of the cell in S phase but also for the time required for its completion. Emerged alongside are new role of these enzymes in relation to the conduct and completion of cell division (mitosis), with inadequate presence of enzymes leading to lesions of the nuclear structure resulting in increased genomic instability and phenotypes resembling cellular senescence. The effect of enzymes on the verge of G2 / M is at least partly attributed to integrated processing of lamin B and we brought that carboxyl mutant protein unable to post-translational processing lead to concentration in intranuclear foci sequestering proteins necessary for proper mitotic progression as the centromeric protein Cenp-F and the phosphorylated form of histone 3, H3(ser10). The loss of progress or fidelity of the mitotic function peaks where the presence of these enzymes is defective in young cells, resulting in the failure of proper formation of mitotic spindle, leading the cell to senescent-like phenotype. Furthermore, we investigated the proper operation of the machinery for post-translational processing of type II transcripts (mRNAs) in senescence. We found poor processing of type II transcripts and this function is linked for the first time with the phosphorylated form of the ATR kinase at serine 428 and accumulation in RNA splicing speckles. This new role of ATR is also linked to the integrity of the nuclear lattice and the redistribution of p-ATR (ser 428) that we unveiled in senescent cells, also accompanied the misconfiguration of the nuclear envelope after downregulation of lamins with small interfering RNA in young cells.

Language

Greek

Subject

Cell Aging

Cell cycle

Human diploid fibroblasts

Lamins

Nucleus

Posttranslational modifications

Senescence

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