Uncoupling of DNA Replication and Centrosome Duplication Cycles Is a Primary Cause of Haploid Instability in Mammalian Somatic Cells

Yoshizawa, Koya; Yaguchi, Kan; Uehara, Ritei

doi:10.3389/fcell.2020.00721

Cited by 7 publications

(5 citation statements)

References 30 publications

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“…The interphase is also divided into the G1 phase (synthesis of RNA and protein), the S phase (DNA synthesis in the nucleus doubles DNA) and the G2 phase (cells further grow and synthesize protein). However, some haploid cells are abnormal during the mitotic phase, skipping the M phase and entering the G1/S phase again, so the DNA content in the cells becomes twice the original [ 64 , 65 ]. Takahashi et al [ 64 ] found that adding Wee1 kinase inhibitor to the culture medium can accelerate the transition from the G2 phase to the M phase of haESCs and prevent the entry of additional G1/S phase.…”

Section: Haploid Diploidizationmentioning

confidence: 99%

Development and application of haploid embryonic stem cells

Wang,

Ma,

Guo

2024

Stem Cell Res Ther

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Haploid cells are a kind of cells with only one set of chromosomes. Compared with traditional diploid cells, haploid cells have unique advantages in gene screening and drug-targeted therapy, due to their phenotype being equal to the genotype. Embryonic stem cells are a kind of cells with strong differentiation potential that can differentiate into various types of cells under specific conditions in vitro. Therefore, haploid embryonic stem cells have the characteristics of both haploid cells and embryonic stem cells, which makes them have significant advantages in many aspects, such as reproductive developmental mechanism research, genetic screening, and drug-targeted therapy. Consequently, establishing haploid embryonic stem cell lines is of great significance. This paper reviews the progress of haploid embryonic stem cell research and briefly discusses the applications of haploid embryonic stem cells.

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Section: Haploid Diploidizationmentioning

confidence: 99%

Development and application of haploid embryonic stem cells

Wang,

Ma,

Guo

2024

Stem Cell Res Ther

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“…96 Eventually, all chromosomes end up in a single daughter cell when the cell completely divides, resulting in the formation of polyploid cell. 163 Improper timing of centrosome separation prior to cell division, both delayed and accelerated centrosome separation, would also lead to the formation of monopolar spindle. 164,165 Loss of ubiquitin-specific peptidase 44 (USP44), a deubiquitinase that localizes at the centrosome, results in incomplete centrosome separation as well as increased monopolar spindle, lagging chromosome, and chromosome bridge.…”

Section: Causes Of Cinmentioning

confidence: 99%

The two sides of chromosomal instability: drivers and brakes in cancer

Hosea,

Hillary,

Naqvi

et al. 2024

Sig Transduct Target Ther

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Chromosomal instability (CIN) is a hallmark of cancer and is associated with tumor cell malignancy. CIN triggers a chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes in chromosomes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to the formation of cells with abnormal number and/or structure of chromosomes. Errors in DNA replication result from abnormal replication licensing as well as replication stress, such as double-strand breaks and stalled replication forks; meanwhile, errors in chromosome segregation stem from defects in chromosome segregation machinery, including centrosome amplification, erroneous microtubule–kinetochore attachments, spindle assembly checkpoint, or defective sister chromatids cohesion. In normal cells, CIN is deleterious and is associated with DNA damage, proteotoxic stress, metabolic alteration, cell cycle arrest, and senescence. Paradoxically, despite these negative consequences, CIN is one of the hallmarks of cancer found in over 90% of solid tumors and in blood cancers. Furthermore, CIN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity, thereby facilitating adaptive resistance to therapies; however, excessive CIN could induce tumor cells death, leading to the “just-right” model for CIN in tumors. Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments. This review provides an overview of causes and consequences of CIN, as well as the paradox of CIN, a phenomenon that continues to perplex researchers. Finally, this review explores the potential of CIN-based anti-tumor therapy.

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“…For further investigating the causality between mitotic defects and haploid developmental abnormalities, it would be ideal to have an experimental condition that restores intact centrosomal control in haploid larvae. Previously, we found that artificial re-coupling of the DNA replication cycle and centrosome duplication cycle by delaying the progression of DNA replication resolved chronic centrosome loss and mitotic defects in human haploid cultured cells (Yoshizawa et al, 2020). Though we tried to restore centrosome loss by treating aphidicolin in haploid larvae, severe toxicity of the compound on haploid larvae after 1 dpf precluded us from testing its effect on centrosome control.…”

Section: Generality Of Haploidy-linked Cellular Defects Across Verteb...mentioning

confidence: 99%

“…Either mitigation of mitotic arrest by spindle assembly checkpoint inactivation or depletion of p53 significantly improved organ growth in haploid larvae, indicating the critical contribution of these cellular defects to haploidy-linked morphogenetic defects. Moreover, haploid zebrafish larvae suffered frequent centrosome loss resulting in mitotic spindle monopolarization, a leading cause of mitotic instability in haploid mammalian cells (1, 2). Haploid larvae also suffered ciliopathy associated with severe centrosome loss.…”

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confidence: 99%

Haploidy-linked cell proliferation defects limit larval growth in Zebrafish

Yaguchi

Saito

Menon

et al. 2022

Preprint

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Haploid embryonic lethality is a common feature in vertebrates. However, the developmental defects and timing of lethality in haploid embryos differ between non-mammalian and mammalian species. Therefore, it remains unknown whether vertebrates share common principles of haploid intolerance. We investigated haploidy-linked defects at the cellular level in gynogenetic haploid zebrafish larvae that manifest characteristic morphogenetic abnormalities. Haploid larvae suffered severe mitotic arrest and irregular upregulation of p53, leading to unscheduled cell death. Either mitigation of mitotic arrest by spindle assembly checkpoint inactivation or depletion of p53 significantly improved organ growth in haploid larvae, indicating the critical contribution of these cellular defects to haploidy-linked morphogenetic defects. Moreover, haploid zebrafish larvae suffered frequent centrosome loss resulting in mitotic spindle monopolarization, a leading cause of mitotic instability in haploid mammalian cells (1, 2). Haploid larvae also suffered ciliopathy associated with severe centrosome loss. Based on our results, we propose the ploidy-linked alteration in centrosome number control as a common principle constraining the allowable ploidy state for normal development in vertebrates.Significance statementHaploid embryos possessing a single chromosome set are invariably lethal in vertebrates. Though haploid intolerance is attributed to imprinting misregulation in mammals, it remains unknown what limits the developmental capacity of haploid non-mammalian vertebrates free from the imprinting constraint. This study revealed the haploidy-linked mitotic misregulation and p53 upregulation as the leading cause of organ growth retardation in haploid zebrafish larvae. Accompanied by these defects, haploid larvae manifested drastic centrosome loss and mitotic spindle monopolarization, defects also limiting the proliferative capacity of haploid mammalian cells. These findings suggest the ploidy-linked alteration in centrosome number control as a common cell-intrinsic principle of haploid intolerance in vertebrates, providing an insight into an evolutionary constraint on allowable ploidy status in animal life cycles.

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Uncoupling of DNA Replication and Centrosome Duplication Cycles Is a Primary Cause of Haploid Instability in Mammalian Somatic Cells

Cited by 7 publications

References 30 publications

Development and application of haploid embryonic stem cells

Development and application of haploid embryonic stem cells

The two sides of chromosomal instability: drivers and brakes in cancer

Haploidy-linked cell proliferation defects limit larval growth in Zebrafish

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