In medio stat virtus : unanticipated consequences of telomere dysequilibrium

Abstract

The integrity of chromosome ends, or telomeres, depends on myriad processes that must balance the need to compact and protect the telomeric, G-rich DNA from detection as a double-stranded DNA break, and yet still permit access to enzymes that process, replicate and maintain a sufficient reserve of telomeric DNA. When unable to maintain this equilibrium, erosion of telomeres leads to perturbations at or near the telomeres themselves, including loss of binding by the telomere protective complex, shelterin, and alterations in transcription and post-translational modifications of histones. Although the catastrophic consequences of full telomere de-protection are well described, recent evidence points to other, less obvious perturbations that arise when telomere length equilibrium is altered. For example, critically short telomeres also perturb DNA methylation and histone post-translational modifications at distal sites throughout the genome. In murine stem cells for example, this dysregulated chromatin leads to inappropriate suppression of pluripotency regulator factors such as Nanog. This review summarizes these recent findings, with an emphasis on how these genome-wide, telomere-induced perturbations can have profound consequences on cell function and fate.This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.

Telomere Replication: Solving Multiple End Replication Problems

“…Somewhat counterintuitively, recent work suggests that telomerase could in fact bind reversed telomeric replication forks in mouse cells deficient for RTEL1 and in this context induce catastrophic telomeric repeat loss ( Margalef et al, 2018 ). While the absence of active telomerase in human somatic cells is an important mechanism to avoid uncontrolled proliferation, it has also been demonstrated that preventing excessive telomere elongation and regulating telomere length at a certain homeostatic level is important for maintaining the functional state of telomeres [reviewed in ( Harrington and Pucci, 2018 )]. It is therefore tempting to speculate that in certain multicellular organisms, repair of telomeric replication fork collapse by telomerase indeed has been evolutionarily counter-selected.…”

Telomere attrition rates are associated with weather conditions and predict productive lifespan in dairy cattle

“…They shorten with the number of cell divisions in vitro as well as in response to oxidative stress and critically short telomeres trigger a DNA damage response that leads to replicative senescence or apoptosis 3 – 5 . In the last decade or so, measures of average telomere length (TL) taken from blood samples have emerged as an exciting biomarker of health across disciplines including biomedicine, epidemiology, ecology and evolutionary biology 6 – 8 . Considerable among- and within-individual variation in TL has been observed, with a general pattern of rapid telomere attrition during early life and a plateau or slower decline thereafter 9 , 10 .…”

Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment

“…More recently, roles distal to the telomere have been described for the telomere shelterin subunit, Rap1, in mice and in budding yeast (Marión et al, 2017;Platt et al, 2013;Song and Johnson, 2018;Vaquero-Sedas and Vega-Palas, 2018). There are other consequences for cell fate beyond senescence, as telomere dysfunction is known to impair stem cell differentiation in numerous contexts (Harrington and Pucci, 2018). For example, eroded telomeres in mESCs impair their ability to fully consolidate a differentiated phenotype in response to all-trans retinoic acid (ATRA) (Pucci et al, 2013).…”