Article Abstract

Telomeric zinc-finger associated protein (TZAP): a new player in telomere diseases?

Authors: Benedetta Donati, Luca Valenti

Abstract

In humans, telomere length homeostasis regulates the balance between cellular immortalization and senescence. In particular, aberrant activation of telomere lengthening allows evasion of cellular senescence leading to uncontrolled replication, both considered major hallmarks of cancer (1). Conversely the regenerative potential of an organ depends on the replicative capacity of its stem cell compartment that is limited by telomere shortening. Indeed, excessive telomere shortening is a condition typical of chronic diseases involving lung and liver (such as fibrosis), blood (aplastic anemia) and skin (2). Due to its fundamental role in maintaining the physiological life-cycle of a cell, telomere homeostasis is tightly regulated by a wide intertwinement of molecular mechanisms. The main process controlling telomere length in somatic cells is “telomere attrition”, that induces the progressive shortening of telomeres at each mitosis, thereby acting as a “mitotic clock” to sense cell aging. When telomeres become critically short (so-called “Hayflick limit”), a DNA-damage program is activated to protect chromosomes’ integrity during cell division, leading to cell senescence or apoptosis. On the contrary, the constitutive expression of telomerase (a ribonuclear enzymatic complex responsible for telomere elongation) allows immortal cells, such as stem or cancer cells, to maintain long telomeres (3). The shelterin proteins complex also participates to this mechanism contributing to telomere protection by binding specifically to telomeres. The main actors of this complex are the telomeric repeat-binding factors 1 and 2 (TRF1-TRF2), that bind double strand DNA conferring telomere stability (2). Furthermore, other mechanisms, such as alternative lengthening of telomeres (ALT) based on homologous recombination (1), are known to participate to telomere elongation independently from telomerase.

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