Bring It to an End: Does Telomeres Size Matter?

Abstract

Telomeres are unique nucleoprotein structures. Found at the edge of each chromosome, their main purpose is to mask DNA ends from the DNA-repair machinery by formation of protective loops. Through life and cell divisions, telomeres shorten and bring cells closer to either cell proliferation crisis or senescence. Beyond this mitotic clock role attributed to the need for telomere to be maintained over a critical length, the very tip of our DNA has been shown to impact transcription by position effect. TPE and a long-reach counterpart, TPE-OLD, are mechanisms recently described in human biology. Still in infancy, the mechanism of action of these processes and their respective genome wide impact remain to be resolved. In this review, we will discuss recent findings on telomere dynamics, TPE, TPE-OLD, and lessons learnt from model organisms.

Keywords: TERRA; TPE; TPE-OLD; aging; telomere.

Figure 1

Telomere length decreases with age. Initial telomere variability comes from the parental telomere length and is modulated both by the father’s age at birth and paternal birth year, a correction factor allowing comparison between different datasets [38]. During development, telomere length decreases abruptly and reaches a steady slow rate of erosion after birth. Telomere attrition is confronted to a critical size corresponding to the senescence stage of the cell. Beyond senescence, cells undergo crisis with continuous telomere length decrease leading to activation of ATM/ATR checkpoint and DNA Damage Response (DDR) pathway activation. Cells surviving to crisis enter in an oncogenic process where telomere length increases thanks to telomerase reactivation or Alternative Lengthening of Telomeres (ALT). In all biological process, a telomere upper length limit is defined by TZAP, avoiding formation of extra-long telomeres.

Figure 2

Telomere nuclear localization and replication timing. Similar to observations made on chromosomes, telomere replication timing is tightly linked to its nuclear localization. In brief, an internal localization correlates with early S-Phase replication and inversely, peripheral localization is associated with late S-Phase replication. Peripheral positioning of telomere is observed for subtelomeres enriched in beta satellite repeats. Through interactions with Lamin-associated partners, a number of telomeres lie in the vicinity of topological domains associated to the lamina (LADs). Importantly, even if an integrative 3D vision of telomere positioning is lacking, telomere replication occurs independently of telomere length.

Figure 3

Gene transcription can be modulated by epigenetic features. (a) Position effect variegaton is caused by presence of heterochromatin regions in the vicinity of a gene. This repressive chromation environment is able to switch off gene expression by heterochromatin marks spreading. Spreading can be blocked by insulator elements bound by CTCF protecting the gene from heterochromatin. (b) Subtelomeric genes expression can be impeded by telomeric heterochromatin spreading through a mechanism called telomere position effect (TPE). Expression can be re-established as telomere shorten, either with age or in pathological conditions. (c) With chromosome folding, telomeres can loop over long distances, bringing together telomeric heterochromatin and gene located in more centromeric locus. Gene expression can be switched on or off, depending on a mechanism not yet fully understood termed TPE-OLD.