Cdc14 phosphatase: warning, no delay allowed for chromosome segregation!

Machín, Félix; Quevedo, Oliver; Ramos-Pérez, Cristina; García-Luis, Jonay

doi:10.1007/s00294-015-0502-1

Cited by 28 publications

(47 citation statements)

References 50 publications

(94 reference statements)

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“…In turn, Esp1/separase is responsible for the cleavage of cohesin required for sister chromatid segregation (Yamamoto et al 1996; Ciosk et al 1998: Uhlmann et al 1999). APC Cdc20 is also required for the eventual release of the Cdc14 phosphatase, essential for mitotic exit (Machin et al 2016). …”

Section: Introductionmentioning

confidence: 99%

A role for the spindle assembly checkpoint in the DNA damage response

Palou

Quintana

2016

Curr Genet

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Spontaneous DNA damage poses a continuous threat to genomic integrity. If unchecked, genotoxic insults result in genomic instability, a hallmark of cancer cells. In eukaryotic cells a DNA Damage Response (DDR) detects and responds to genotoxic stress, acting as an anti-cancer barrier in humans. Among other actions, the DDR blocks the segregation of incompletely replicated or damaged chromosomes, thus preventing aneuploidy. In a work aimed at better understanding such S-M control, we recently showed that cells block anaphase through different control pathways. The S phase checkpoint kinase Mec1/ATR inhibits mitotic Cyclin Dependent Kinase activity through effector kinases Swe1/Wee1 and Rad53/Chk2. Cells also stabilize the levels of Pds1/securin to block sister chromatid segregation in response to DNA damage. We show here that Pds1/securin abundance is still secured when the S phase checkpoint response is fully abrogated in mec1/ATR tel1/ATM double null mutants. When such cells are exposed to genotoxic stress, Pds1/securin is stabilized in a spindle assembly checkpoint (SAC) dependent manner. Disruption of the SAC and the S phase checkpoint together, allows chromosome segregation in the presence of DNA damage or replication stress. Our results place the SAC as a part of the DDR, which appears to count on different, independent control layers to preserve genomic integrity when chromosome replication is challenged.

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Section: Introductionmentioning

confidence: 99%

A role for the spindle assembly checkpoint in the DNA damage response

Palou

Quintana

2016

Curr Genet

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“…One interpretation of the strong bias for T-LOH events relative to I-LOH events (76 terminal and 3 interstitial) is that DSBs are repaired primarily through BIR (Fig. 5E) [11, 51]. In many previous studies, I-LOH represented a very significant fraction of the total LOH events.…”

Section: Discussionmentioning

confidence: 93%

“…Even though we did not prove that all survivors came from a MC (i.e., they went through anaphase), the results shown in Figs 1-5, together with previous findings [13,24,25] lead us to conclude that most of these survivors likely came from a top2 MC. Indeed, many of the observed chromosome variations and rearrangements can be best explained if cells go through anaphase in the absence of proper sister chromatid disjunction [11]. One interpretation of the strong bias for T-LOH events relative to I-LOH events (76 terminal and 3 interstitial) is that DSBs are repaired primarily through BIR (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cytological and genetic consequences for the progeny of a mitotic catastrophe provoked by Topoisomerase II deficiency

Ramos-Pérez

Dominska

Anaissi-Afonso

et al. 2019

Preprint

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25Topoisomerase II (Top2) removes topological linkages between replicated chromosomes. 26Top2 inhibition leads to mitotic catastrophe (MC) when cells unsuccessfully try to split their 27 genetic material between the two daughter cells. Herein, we have characterized the fate of 28 these daughter cells in the budding yeast. Clonogenic and microcolony experiments, in 29 combination with vital and apoptotic stains, showed that 75% of daughter cells become 30 senescent in the short term; they are unable to divide but remain alive. Decline in cell vitality 31 then occurred, yet slowly, uncoordinatedly when comparing pairs of daughters, and 32 independently of the cell death mediator Mca1/Yca1. Furthermore, we showed that 33 senescence can be modulated by ploidy, suggesting that gross chromosome imbalances 34 during segregation may account for this phenotype. Indeed, we found that diploid long-term 35 survivors of the MC are prone to genomic imbalances such as trisomies, uniparental disomies 36 and terminal loss of heterozygosity (LOH), the latter affecting the longest chromosome arms. 37 38 39 40 41 86show that most of the top2 MC progeny lose their ability to divide. Interestingly, these 87 daughter cells do not die abruptly but undergo a slow decline in cell vitality over several 88 5 hours. The patterns of cell death point towards an ACD, which was genetically corroborated 89 with mutants for the main apoptotic pathway. We have also used heterozygous diploids to 90 diagnose chromosome rearrangements in the surviving progeny, and we found genomic 91 footprints that include uniparental disomy and terminal loss of heterozygosity in the longest 92 chromosome arms. We conclude that (i) most top2 daughter cells become senescent in the 93 short-term while eventually dying by ACD; and (ii) the surviving offspring frequently carry 94 genomic rearrangements expected from transiting through anaphase with intertwined sister 95 chromatids. 96 97 98 6 RESULTS.99 Seventy five percent of the progeny of a top2-5 mitotic catastrophe is inviable. 100 We have recently reported that the top2-5 thermosensitive mutant undergoes timely 101 progression through the cell cycle until a MC occurs in late anaphase [25]. Importantly, top2-102 5 gives a clear point-of-no-return in the MC phenotype because cytokinesis makes the top2-5 103 anaphase bridges collapse irreversibly. In many ways, this MC is similar to other previously 104 studied top2 conditional alleles [13,24], although top2-5 provides a better synchrony for the 105 MC since a larger percentage of cells quickly sever the anaphase bridge [25]. 106 We performed single-cell videomicroscopy on agar plates through long-range 107 objectives and found that mother and daughter cells struggled to rebud (the most obvious 108 yeast signal for a new cell cycle) without Top2 (Fig. 1A) [25]. Whereas TOP2 unbudded 109 (G 1 /G 0 ) cells were able to form microcolonies of around 10 cell bodies after 6 h at 37 ºC, 110 top2-5 cells stopped dividing at either 2 (~65%) or 3 (~20%) cell bodies ( Fig....

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“…During ( (Machín et al 2016). DNA damage (DSBs) locally mobilizes the affected chromatin through decondensation, so the histone-poor signal in de novo chromatin bridges, and globally accelerate loci movement.…”

Section: Ratio Cin8-p/cin8mentioning

confidence: 99%

DNA damage in telophase leads to coalescence between segregated sister chromatid loci

Ayra-Plasencia¹,

Machín

2018

Preprint

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The generation of DNA double strand breaks (DSBs) pose a high risk for the maintenance of the genome. Cells repair DSBs through two major mechanisms: nonhomologous end joining (NHEJ) and homologous recombination (HR). HR is usually preferred when a sister chromatid is available, thus cells have coupled the activity of the cycling dependent kinase (CDK) to the selection of HR (Symington et al. 2014).Paradoxically, there is a window in the cell cycle where CDK is high despite a sister chromatid is not physically available for HR: late anaphase/telophase. We have here studied in budding yeast the response to DSBs generated in telophase by means of the radiomimetic drug phleomycin. We first show that phleomycin treatment activates the DNA damage response and leads to a delay in the telophase-to-G1 transition.Outstandingly, we also found a partial reversion of sister chromatid segregation, which includes approximation of spindle pole bodies (SPBs) and sister centromeres, de novo formation of anaphase bridges, trafficking of DNA back and forth through the cytokinetic plane and events of coalescence between segregated sister telomeres. We importantly show that phleomycin promotes a massive change in the structure and dynamic of mitotic microtubules (MTs), which coincides with dephosphorylation and re-localization of kinesin-5 Cin8. We propose that anaphase is not entirely irreversible and that there could still be a window to repair DSBs using the sister chromatid after segregation.

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Cdc14 phosphatase: warning, no delay allowed for chromosome segregation!

Cited by 28 publications

References 50 publications

A role for the spindle assembly checkpoint in the DNA damage response

A role for the spindle assembly checkpoint in the DNA damage response

Cytological and genetic consequences for the progeny of a mitotic catastrophe provoked by Topoisomerase II deficiency

DNA damage in telophase leads to coalescence between segregated sister chromatid loci

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