Rb analog Whi5 regulates G1 to S transition and cell size but not replicative lifespan in budding yeast

Crane, Matthew M.; Tsuchiya, Mitsuhiro; Blue, Ben; Almazan, Jared; Chen, Kenneth L.; Duffy, Siobhan R.; Golubeva, Alexandra; Grimm, Annaiz M.; Guard, Alison M.; Hill, Shauna A.; Huynh, Ellen; Kelly, Ryan; Kiflezghi, Michael G.; Kim, Hyunsung D; Mitchell, Lee; Lee, Ting-I.; Li, Jiayi; Nguyen, Bao; Whalen, Riley; Yeh, Feng Y.; McCormick, Mark; Kennedy, Brian K.; Delaney, Joe R.; Kaeberlein, Matt

doi:10.1016/j.tma.2019.10.002

“…Accordingly, alteration of the mitotic cycle in S/G2/M, due for instance to activation of checkpoint mechanisms, might provoke increased Whi5 levels, which in turn would induce subsequent cell-cycle alterations, enabling a self-regulatory loop that would propagate throughout the cell linage. Such activation of checkpoints has been described to play a role in mitotic catastrophe during late aging 64 . Our work suggest that it may be a more common phenomenon, potentially being triggered in any stage of replicative life span, and explaining the high proliferative heterogeneity of cell populations.…”

Section: Discussionmentioning

confidence: 99%

Cell-cycle regulator Whi5 shapes proliferative heterogeneity in clonal populations

Delgado-Román

¹

,

Delgado-Ramos

²

,

Muñoz-Centeno

³

2023

Preprint

0

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Clonal cultures exhibit phenotypic variation in spite of being composed of genetically identical cells under equal environmental conditions. Proliferation rate is one of the characters that have been described to show this heterogeneity, but the mechanisms underlying this phenomenon are still poorly understood. Cell cycle regulation controls proliferative capacity and previous transcriptomic studies revealed that budding yeast microcolonies with low proliferation rates display high levels of the G1-S transition inhibitor Whi5. This regulator, which, in budding yeast, plays a similar role as Retinoblastoma protein in mammalian cells, has been also linked to replicative aging in late steps of mother cells lifespan. In this work, we combined single cell microencapsulation with confocal microscopy to study heterogeneity in clonal cultures. Using this new method, we found that a significant proportion of slow-growing microcolonies are founded by mother cells with a short number of cell cycles. We also found that the reduction in the proliferation capacity of microcolonies founded by young mother cells is related to the expression levels of Whi5, which increases with mother cell age since early stages. Our results establish that stably reduced proliferation is not exclusively linked to old mother cells and indicate that cell age contributes to proliferation heterogeneity by modulating cell cycle regulation.

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“…For instance, Cln3 in association with cyclin-dependent kinase (Cln3-CDK) is an early inactivator of Whi5 (reviewed Fisher, 2016; Ewald, 2018; Li et al, 2021). Whi5, the yeast homolog of human retinoblastoma protein (Crane et al, 2019), is an inhibitor of the SBF-dependent transcription of genes that are required for the transition into S phase (Talerak et al, 2017; Teufel et al, 2019). SBF (and MBF) activation results in Cln1 and Cln2 upregulation, leading to Cln1-CDK and Cln2-CDK complexes that further inactivate Whi5 and provide a positive feedback mechanism to promote START.…”

Section: Discussionmentioning

confidence: 99%

G1-Cyclin2 (Cln2) promotes chromosome hypercondensation in eco1/ctf7 rad61 null cells during hyperthermic stress in Saccharomyces cerevisiae

Buskirk

¹

,

Skibbens

²

2022

Preprint

0

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Eco1/Ctf7 is a highly conserved acetyltransferase that activates cohesin complexes and is critical for sister chromatid cohesion, chromosome condensation, DNA damage repair, nucleolar integrity, and gene transcription. Mutations in the human homolog of ECO1 (ESCO2/EFO2), or in genes that encode cohesin subunits, result in severe developmental abnormalities and intellectual disabilities referred to as Roberts Syndrome (RBS) and Cornelia de Lange Syndrome (CdLS), respectively. In yeast, deletion of ECO1 results in cell inviability. Co-deletion of RAD61 (WAPL in humans), however, produces viable yeast cells. These eco1 rad61 double mutants, however, exhibit a severe temperature-sensitive growth defect, suggesting that Eco1 or cohesins respond to hyperthermic stress through a mechanism that occurs independent of Rad61. Here, we report that deletion of the G1 cyclin CLN2 rescues the temperature sensitive lethality otherwise exhibited by eco1 rad61 mutant cells, such that the triple mutant cells exhibit robust growth over a broad range of temperatures. While Cln1, Cln2 and Cln3 are functionally redundant G1 cyclins, neither CLN1 nor CLN3 deletions rescue the temperature-sensitive growth defects otherwise exhibited by eco1 rad61 double mutants. We further provide evidence that CLN2 deletion rescues hyperthermic growth defects independent of START and impacts the state of chromosome condensation. These findings reveal novel roles for Cln2 that are unique among the G1 cyclin family and appear critical for cohesin regulation during hyperthermic stress.

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“…For instance, Cln3 in association with cyclin-dependent kinase (Cln3-CDK) is an early inactivator of Whi5 (reviewed Fisher 2016 ; Ewald 2018 ; Li et al 2021 ). Whi5, the yeast homolog of human retinoblastoma protein ( Crane et al 2019 ), is an inhibitor of the SBF-dependent transcription of genes that are required for the transition into S phase ( Talarek et al 2017 ; Teufel et al 2019 ). SBF (and MBF) activation results in Cln1 and Cln2 upregulation, leading to Cln1-CDK and Cln2-CDK complexes that further inactivate Whi5 and provide a positive feedback mechanism to promote START.…”

Section: Discussionmentioning

confidence: 99%

G1-Cyclin2 (Cln2) promotes chromosome hypercondensation in eco1/ctf7 rad61 null cells during hyperthermic stress in Saccharomyces cerevisiae

Buskirk

¹

,

Skibbens

²

2022

G3 Genes|Genomes|Genetics

0

View full text Add to dashboard Cite

Eco1/Ctf7 is a highly conserved acetyltransferase that activates cohesin complexes and is critical for sister chromatid cohesion, chromosome condensation, DNA damage repair, nucleolar integrity, and gene transcription. Mutations in the human homolog of ECO1 (ESCO2/EFO2), or in genes that encode cohesin subunits, result in severe developmental abnormalities and intellectual disabilities referred to as Roberts Syndrome (RBS) and Cornelia de Lange Syndrome (CdLS), respectively. In yeast, deletion of ECO1 results in cell inviability. Co-deletion of RAD61 (WAPL in humans), however, produces viable yeast cells. These eco1 rad61 double mutants, however, exhibit a severe temperature-sensitive growth defect, suggesting that Eco1 or cohesins respond to hyperthermic stress through a mechanism that occurs independent of Rad61. Here, we report that deletion of the G1 cyclin CLN2 rescues the temperature sensitive lethality otherwise exhibited by eco1 rad61 mutant cells, such that the triple mutant cells exhibit robust growth over a broad range of temperatures. While Cln1, Cln2 and Cln3 are functionally redundant G1 cyclins, neither CLN1 nor CLN3 deletions rescue the temperature-sensitive growth defects otherwise exhibited by eco1 rad61 double mutants. We further provide evidence that CLN2 deletion rescues hyperthermic growth defects independent of START and impacts the state of chromosome condensation. These findings reveal novel roles for Cln2 that are unique among the G1 cyclin family and appear critical for cohesin regulation during hyperthermic stress.

show abstract

Rb analog Whi5 regulates G1 to S transition and cell size but not replicative lifespan in budding yeast

Cited by 5 publications

References 31 publications

Cell-cycle regulator Whi5 shapes proliferative heterogeneity in clonal populations

Cell-cycle regulator Whi5 shapes proliferative heterogeneity in clonal populations

G1-Cyclin2 (Cln2) promotes chromosome hypercondensation in eco1/ctf7 rad61 null cells during hyperthermic stress in Saccharomyces cerevisiae

G1-Cyclin2 (Cln2) promotes chromosome hypercondensation in eco1/ctf7 rad61 null cells during hyperthermic stress in Saccharomyces cerevisiae

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