Adaptation in replicative senescence: a risky business

Coutelier, Héloïse; Xu, Zhou

doi:10.1007/s00294-019-00933-7

Cited by 13 publications

(20 citation statements)

References 70 publications

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“…Arrested cells that do not successfully repair the damage may eventually adapt to DNA damage, a process that allows for cell division despite the presence of unrepaired DNA damage (Lee, Moore, et al, 1998;Sandell & Zakian, 1993;Toczyski, Galgoczy, & Hartwell, 1997). Telomerase-negative cells that activate the DNA damage checkpoint are also able to adapt after extended arrest (Coutelier et al, 2018;Coutelier & Xu, 2019). Adapted cells retain a partially active checkpoint, which indicates that the initially sensed damage is still present and makes them prone to further repair or adaptation.…”

Section: Activation Of the Dna Damage Checkpoint Dna Repair And Amentioning

confidence: 99%

The many types of heterogeneity in replicative senescence

Teixeira

2019

Yeast

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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.

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Section: Activation Of the Dna Damage Checkpoint Dna Repair And Amentioning

confidence: 99%

The many types of heterogeneity in replicative senescence

Teixeira

2019

Yeast

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“…After prolonged arrests, checkpoints such as the DNA damage checkpoint or the spindle assembly checkpoint (SAC) are overridden in the continued presence of errors, which is associated with genomic instability and aneuploidy in yeast and mammalian cells. 3,[12][13][14][15][16] (We opt for the more general term 'override' in place of 'adaptation', 'slippage', or 'leakage' 3 . )…”

Section: Introductionmentioning

confidence: 99%

“…Many researchers have pointed out that checkpoints may balance opposing demands on repair success and speed. 7,12,16,18 However, these ideas have so far not been developed into a quantitative theory of checkpoint strategies, which could be supported by experimental measurements of the parameters of the theory and by validation of new predictions. Chemical kinetic models represent the dynamics of the molecular components of checkpoints [19][20][21] but they do not indicate potential strategies for checkpoints in an obvious manner as they primarily describe the state of the system in time.…”

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confidence: 99%

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Optimizing checkpoint strategies based on first principles predicts experimental DNA damage checkpoint override times

Sadeghi

Dervey

Gligorovski

et al. 2020

Preprint

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Why biological quality-control systems fail is often mysterious. Specifically, checkpoints such as the DNA damage checkpoint or the spindle assembly checkpoint are overriden after prolonged arrests allowing cells to continue dividing despite the continued presence of errors. Although critical for biological systems, checkpoint override is poorly understood quantitatively by experiment or theory. Override may represent a trade-off between risk and speed, a fundamental principle explaining biological phenomena. Here, we derive the first, general theory of optimal checkpoint strategies, balancing risk and opportunities for growth. We demonstrate that the mathematical problem of finding the optimal strategy maps onto the question of calculating the optimal absorbing boundary for a random walk, which we show can be solved efficiently recursively. The theory predicts the optimal override strategy without any free parameters based on two inputs, the statistics i) of error correction and ii) of survival. We apply the theory to the prominent example of the DNA damage checkpoint in budding yeast (Saccharomyces cerevisiae) experimentally. Using a novel fluorescent construct which allowed cells with DNA breaks to be isolated by flow cytometry, we quantified i) the probability distribution function of repair for a double-strand DNA break (DSB), including for the critically important, rare events deep in the tail of the distribution, as well as ii) the survival probability if the checkpoint was overridden. Based on these two measurements, the optimal checkpoint theory predicted remarkably accurately the DNA damage checkpoint override times as a function of DSB numbers, which we measured precisely at the single-cell level. Our multi-DSB results refine well-known bulk culture measurements and show that override is a more general phenomenon than previously thought. Further, we show for the first time that override is an advantageous strategy in cells with wild-type DNA repair genes. The universal nature of the balance between risk and self-replication opportunity is in principle relevant to many other systems, including other checkpoints, developmental decisions, or reprogramming of cancer cells, suggesting potential further applications of the theory.

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“…Despite these mechanisms, if the DNA damage remains, the checkpoints are overridden, and the cell exits metaphase [4]. The persistence of unrepaired double-strand breaks (DSBs) at metaphase is particularly problematic due to the formation of chromosome fragments, one of which lacks a telomere and the other lacking a centromere and a telomere.…”

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confidence: 99%

Kinetochore-independent mechanisms of sister chromosome separation

Vicars

Karg

Warecki

et al. 2020

Preprint

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Although centromeres play a key role in sister chromatid separation and segregation, mitotic transmission of chromosome fragments lacking a centromere (acentrics) can be successful. In Drosophila neuroblasts, acentric chromosomes undergo delayed, but successful transmission revealing the existence of kinetochore-independent mechanisms driving transmission. In spite of delayed sister chromatid separation, bulk cohesin removal from the acentric is not delayed, suggesting factors other than cohesin are responsible for the delay. In contrast to intact kinetochore-bearing chromosomes, we discovered that acentrics align parallel as well as perpendicular to the mitotic spindle. In addition, sister acentrics undergo unconventional patterns of separation. For example, rather than the simultaneous separation of sisters, acentrics oriented parallel to the spindle often slide past one another toward opposing poles. To identify the mechanisms driving acentric separation, we screened 117 RNAi gene knockdowns for synthetic lethality with acentric chromosome fragments. In addition to well-established DNA repair and checkpoint mutants, this candidate screen identified synthetic lethality with X-chromosome-derived acentric fragments in knockdowns of Greatwall (cell cycle kinase), EB1 (plus-end tracking protein), and Map205 (microtubule-stabilizing protein). Additional image-based screening revealed that reductions in Topoisomerase II levels disrupted sister acentric separation. Intriguingly, live imaging revealed that knockdowns of EB1, Map205, and Greatwall preferentially disrupted the sliding mode of sister acentric separation. In spite of these failures in acentric separation, acentrics incorporated into daughter nuclei and there was no increase in micronuclei formation. Based on our analysis of EB1 localization and knockdown phenotypes, we propose that in the absence of a kinetochore, microtubule plus-end dynamics provide the force to resolve DNA catenations required for sister separation.AUTHOR SUMMARYCentromeres, the site on the chromosomes to which microtubules attach driving the separation and segregation of replicated sister chromosomes, have been viewed as essential for proper cell division and accurate transmission of chromosomes into daughter cells. However previous studies demonstrated that sister chromosomes lacking a centromere (acentrics) often undergo separation, segregation and transmission. Here we demonstrate that sister acentrics are held together through DNA intertwining. During anaphase, acentric sister separation is achieved through Topoisomerase activity, an enzyme that resolves these DNA linkages, as well as forces generated on the acentrics by the growing ends of highly dynamic microtubule polymers. We found acentric sister chromatids display unique patterns of separation using mechanisms independent of the centromere. Additionally, we identified the specific microtubule-associated proteins required for the successful mitotic transmission of acentric chromosomes to daughter cells. These studies reveal unsuspected, distinct forces that likely act on all chromosomes during mitosis independent of centromere-microtubule attachments.

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Adaptation in replicative senescence: a risky business

Cited by 13 publications

References 70 publications

The many types of heterogeneity in replicative senescence

The many types of heterogeneity in replicative senescence

Optimizing checkpoint strategies based on first principles predicts experimental DNA damage checkpoint override times

Kinetochore-independent mechanisms of sister chromosome separation

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