To Fix or Not to Fix: Maintenance of Chromosome Ends Versus Repair of DNA Double-Strand Breaks

Abstract

Early work by Muller and McClintock discovered that the physical ends of linear chromosomes, named telomeres, possess an inherent ability to escape unwarranted fusions. Since then, extensive research has shown that this special feature relies on specialized proteins and structural properties that confer identity to the chromosome ends, thus allowing cells to distinguish them from intrachromosomal DNA double-strand breaks. Due to the inability of conventional DNA replication to fully replicate the chromosome ends and the downregulation of telomerase in most somatic human tissues, telomeres shorten as cells divide and lose this protective capacity. Telomere attrition causes the activation of the DNA damage checkpoint that leads to a cell-cycle arrest and the entering of cells into a nondividing state, called replicative senescence, that acts as a barrier against tumorigenesis. However, downregulation of the checkpoint overcomes this barrier and leads to further genomic instability that, if coupled with re-stabilization of telomeres, can drive tumorigenesis. This review focuses on the key experiments that have been performed in the model organism Saccharomyces cerevisiae to uncover the mechanisms that protect the chromosome ends from eliciting a DNA damage response, the conservation of these pathways in mammals, as well as the consequences of their loss in human cancer.

The multistep path to replicative senescence onset: zooming on triggering and inhibitory events at telomeric DNA

“…An intriguing hypothesis suggests that dysfunctional telomeres are not direct inducers of replicative senescence, but they rather lead to a wider genome instability and a strong DDR activation that together trigger senescence onset (Figure 1). Accordingly, adaptation to DNA damage is a potent source of genome instability (Pizzul et al, 2022), which may accumulate upon successive transient arrests. In human cells, telomere uncapping can be tolerated leading to a transient arrest (Ghadaouia et al, 2018;Ghadaouia et al, 2021), but subsequent cell divisions with dysfunctional telomeres likely fuel genome instability and lead to a stable senescence-associated proliferation arrest (Ghadaouia et al, 2021).…”

“…The budding yeast S. cerevisiae took the stage as a tool for the study of telomere biology very early in the history (reviewed in Casari et al, 2022 ). Thanks to the high evolutive conservation of telomere biology, it quickly became a model organism for understanding the mechanisms of i) telomere maintenance, ii) replicative senescence onset, and iii) replicative senescence bypass.…”

“…Specialized nucleoprotein complexes, called telomeres, carry out these crucial functions. Telomeres consist of short tandem DNA repeats (e.g., TTAGGG in mammals) and of a group of specialized proteins, known as “shelterin” in mammals, which regulate telomere functions (reviewed in de Lange, 2018 ; Casari et al, 2022 ).…”

“…Replicative senescence is a permanent proliferation arrest triggered by several events, including telomere shortening and/or deprotection. It has long been considered as a tumor suppressor mechanism because it limits the proliferation of cells with oncogenic mutations and it prevents genome instability caused by excessive telomere shortening and deprotection (reviewed in Maciejowski and de Lange, 2017 ; Casari et al, 2022 ). Recent findings, however, highlight a positive role for replicative senescence in cancer evolution, related to the secretory functions of senescent cells ( Yang et al, 2021 ).…”

A comprehensive map of hotspots of de novo telomere addition inSaccharomyces cerevisiae

“…Indeed, similar to telomeres, enzymatic resection at a DSB generates 3’ overhangs that can serve as substrates for homologous recombination. The specific sequence of the 3’ overhang at telomeres distinguishes it from 3’ overhangs generated by resection at a double strand break, thereby enforcing different outcomes at these otherwise similar structures (telomere elongation versus DNA repair, respectively; reviewed in Casari et al 2022; Doksani & de Lange, 2014). However, rarely, the 3’ overhang generated at a DSB is recognized by telomerase, resulting in addition of a new or de novo telomere (reviewed in Hoerr et al 2021; Pennaneach et al 2006).…”