The many types of heterogeneity in replicative senescence

Abstract

Replicative senescence, which is induced by telomere shortening, underlies the loss of regeneration capacity of organs and is ultimately detrimental to the organism. At the same time, it is required to protect organisms from unlimited cell proliferation that may arise from numerous stimuli or deregulations. One important feature of replicative senescence is its high level of heterogeneity and asynchrony, which promote genome instability and senescence escape. Characterizing this heterogeneity and investigating its sources are thus critical to understanding the robustness of replicative senescence. Here we review the different aspects of senescence driven by telomere attrition that are subject to variation in Saccharomyces cerevisiae, the current understanding of the molecular processes at play, and the consequences of heterogeneity in replicative senescence.

Keywords: DNA damage checkpoint; heterogeneity; replicative senescence; telomerase; telomere.

Figure 1

(a) Differences in proliferation observed in pairs of sister telomerase‐negative cells after budding yeast meiosis, (b) budding yeast mitosis, and (c) human fibroblast mitosis. In theory, the lengths of telomeres in a pair of mother and daughter cells after mitosis are similar (but not equal, see Figure 3). (a and b) In contrast, telomere lengths are more frequently different among meiotic products because of independent segregation of chromosomes in meiosis. Proliferation potential in the progenies of telomerase‐negative pairs of cells from a meiotic product is thus more variable than for telomerase‐negative pairs of mitotically divided mother and daughter cells (Enomoto, Glowczewski, & Berman, 2002; Xu, Duc, Holcman, & Teixeira, 2013). (c) In contrast, in human fibroblasts, the onset of senescence is variable among pairs of daughter cells derived from mitosis (Jones, Whitney, & Smith, 1985). This suggests that replicative senescence of human cells is accompanied by events that might amplify heterogeneity. – and + indicate telomerase negative and telomerase positive, respectively.

Figure 2

Heterogeneity at the level of single‐cell lineages. (a) Many telomerase‐negative cell lineages, defined here as consecutive cell divisions upon telomerase inactivation until irreversible cell cycle arrest, undergo senescence in a single switch from proliferative to arrested state. (b) In contrast, other cell lineages are likely subject to accidental damage at telomeres that triggers the DNA damage checkpoint and DNA repair mechanisms. The frequent failure of repair mechanisms, combined with the relative ease of bypassing checkpoints by adaptation, then leads to a cascade of genome instability and a multiplicity of cell fates. Modified from Coutelier et al., (2018)

Figure 3

The DNA end replication problem and progressive telomere shortening contain an intrinsic mechanism that generates length asymmetry (modified from Soudet, Jolivet, & Teixeira, 2014). Telomeres end with a 3′‐overhang of 5–10 nucleotides in Saccharomyces cerevisiae. Passage of the replication fork leads to two newly replicated telomeres of different lengths. The telomere replicated by the lagging strand machinery naturally bears a 3′‐overhang by the removal of the last RNA primer of the Okazaki fragment, whereas the telomere replicated by the leading strand machinery requires additional resection and fill‐in steps to regenerate a 3′‐overhang