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.

Telomere Replication: Solving Multiple End Replication Problems

“…It is thought that this event is triggered by stresses encountered during DNA replication and the resulting single critically short telomere is enough to cause growth arrest ( Abdallah et al, 2009 ; Khadaroo et al, 2009 ; Xu et al, 2013 ). Consistent with this, telomerase inactivation rapidly exposes problems associated with telomeric replication stress, even before bulk telomere shortening reaches a critical point ( Ijpma and Greider, 2003 ; Khadaroo et al, 2009 ; Jay et al, 2016 ; Xu and Teixeira, 2019 ). Observation of the dynamics of individual telomerase-negative cell lineages very early after inactivation of telomerase has recently been made possible by using a microfluidics device coupled with an inducible telomerase-null mutant.…”

“…In the absence of telomerase, multiple repair mechanisms involving checkpoint mediators, recombination factors, DNA damage adaptors, and post-replication repair are required for telomere healing [reviewed in ( Simon M. N. et al, 2016 )]. A variety of factors in these different pathways have been identified as delaying senescence, as upon their removal the onset of senescence is accelerated [reviewed in ( Simon M. N. et al, 2016 ; Xu and Teixeira, 2019 )]. Further supporting the idea that replication stress is unmasked in the absence of telomerase, elevation of dNTP pools (facilitating replication) alleviates the early senescence seen in the absence of DNA damage adaptors ( Jay et al, 2016 ).…”

Cellular senescence in hepatocellular carcinoma induced by a long non-coding RNA-encoded peptide PINT87aa by blocking FOXM1-mediated PHB2

“…Cellular senescence is an anti-tumor program, which induces proliferation arrest in tumor cells 1 . In general, there are two types of senescence, replicative senescence (RS) caused by telomere shortening or dysfunction 2 , 3 and premature senescence triggered by stress, including oncogenes (oncogene-induced senescence, OIS) 4 , 5 and DNA damage response (DDR) 6 . Replicative and premature senescence exhibit similar phenotypes and molecular characteristics 7 .…”

Targeting cellular senescence based on interorganelle communication, multilevel proteostasis, and metabolic control

“…that contribute to induction and maintenance of the senescent state are conserved in evolution. Thus, simple and easy‐to‐manipulate model organisms such as the yeast Saccharomyces cerevisiae ( S. cerevisiae ) or the nematode Caenorhabditis elegans ( C. elegans ) are frequently used to elucidate fundamental aspects of cell damage and disruption of homeostasis, which promote senescence in vertebrates [ 10 , 11 , 12 , 13 , 14 , 15 ]. However, there is little evidence for senescence in these simple models, which are evolutionarily quite distant from humans.…”