Predicting stem cell fate changes by differential cell cycle progression patterns

The lysine acetyltransferase 6 (KAT6) histone acetyltransferase (HAT) complexes are highly conserved from yeast to higher organisms. They acetylate histone H3 and other nonhistone substrates and are involved in cell cycle regulation and stem cell maintenance. In addition, the human KAT6 HATs are recurrently mutated in leukemia and solid tumors. Therefore, it is important to understand the mechanisms underlying the regulation of KAT6 HATs and their roles in cell cycle progression. In this minireview, we summarize the identification and analysis of the KAT6 complexes and discuss the regulatory mechanisms governing their enzymatic activities and substrate specificities. We further focus on the roles of KAT6 HATs in regulating cell proliferation and stem cell maintenance and review recent insights that aid in understanding their involvement in human diseases.

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Coordination between Cell Cycle Progression and Cell Fate Decision by the p53 and E2F1 Pathways in Response to DNA Damage

Journal of Biological Chemistry ◽

10.1074/jbc.m110.134650 ◽

2010 ◽

Vol 285 (41) ◽

pp. 31571-31580 ◽

Cited By ~ 36

Author(s):

Xiao-Peng Zhang ◽

Feng Liu ◽

Wei Wang

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Fate ◽

Cell Cycle Progression ◽

Cell Fate Decision ◽

Cycle Progression ◽

Fate Decision

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Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins

Open Biology ◽

10.1098/rsob.140156 ◽

2015 ◽

Vol 5 (3) ◽

pp. 140156 ◽

Cited By ~ 32

Author(s):

Didier J. Colin ◽

Karolina O. Hain ◽

Lindsey A. Allan ◽

Paul R. Clarke

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Protein Kinases ◽

Cell Fate ◽

Dna Damage Response ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Anti Cancer ◽

Damage Response ◽

Microtubule Poisons

Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-x L by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

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The adult stem cell marker Musashi-1 modulates endometrial carcinoma cell cycle progression and apoptosisviaNotch-1 and p21WAF1/CIP1

International Journal of Cancer ◽

10.1002/ijc.25856 ◽

2011 ◽

Vol 129 (8) ◽

pp. 2042-2049 ◽

Cited By ~ 54

Author(s):

Martin Götte ◽

Burkhard Greve ◽

Reinhard Kelsch ◽

Heike Müller-Uthoff ◽

Kristin Weiss ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cell ◽

Endometrial Carcinoma ◽

Cell Cycle Progression ◽

Carcinoma Cell ◽

Adult Stem Cell ◽

Stem Cell Marker ◽

Cell Marker ◽

Cycle Progression ◽

Endometrial Carcinoma Cell

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A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development

Current Biology ◽

10.1016/j.cub.2017.02.015 ◽

2017 ◽

Vol 27 (6) ◽

pp. 905-913 ◽

Cited By ~ 57

Author(s):

Kristina Ames ◽

Dayse S. Da Cunha ◽

Brenda Gonzalez ◽

Marina Konta ◽

Feng Lin ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Stem Cell ◽

Cell Cycle Progression ◽

Germline Development ◽

Cycle Progression ◽

Stem Cell Proliferation

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Excess histone H3 is a Chk1 inhibitor that controls embryonic cell cycle progression

10.1101/2020.06.09.142414 ◽

2020 ◽

Author(s):

Yuki Shindo ◽

Amanda A. Amodeo

Keyword(s):

Cell Cycle ◽

Cell Fate ◽

Cell Cycle Progression ◽

Histone H3 ◽

Embryonic Cell ◽

Cycle Progression ◽

Cell Cycles ◽

Embryonic Cell Cycle

AbstractThe early embryos of many species undergo a switch from rapid, reductive cleavage divisions to slower, cell fate-specific division patterns at the Mid-Blastula Transition (MBT). The maternally loaded histone pool is used to measure the increasing ratio of nuclei to cytoplasm (N/C ratio) to control MBT onset, but the molecular mechanism of how histones regulate the cell cycle has remained elusive. Here, we show that excess histone H3 inhibits the DNA damage checkpoint kinase Chk1 to promote cell cycle progression in the Drosophila embryo. We find that excess H3-tail that cannot be incorporated into chromatin is sufficient to shorten the embryonic cell cycle and reduce the activity of Chk1 in vitro and in vivo. Removal of the Chk1 phosphosite in H3 abolishes its ability to regulate the cell cycle. Mathematical modeling quantitatively supports a mechanism where changes in H3 nuclear concentrations over the final cell cycles leading up to the MBT regulate Chk1-dependent cell cycle slowing. We provide a novel mechanism for Chk1 regulation by H3, which is crucial for proper cell cycle remodeling during early embryogenesis.

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Cell cycle exit and stem cell differentiation are coupled through regulation of mitochondrial activity in the Drosophila testis

10.1101/2021.01.12.426342 ◽

2021 ◽

Author(s):

Diego Sainz de la Maza ◽

Silvana Hof-Michel ◽

Lee Phillimore ◽

Christian Bökel ◽

Marc Amoyel

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Stem Cell ◽

Cell Cycle Progression ◽

Stem Cell Differentiation ◽

Mitochondrial Activity ◽

Self Renewal ◽

Cycle Progression ◽

Cell Identity ◽

Drosophila Testis

AbstractStem cells maintain tissue homeostasis by proliferating to replace cells lost to damage or natural turnover. Whereas stem and progenitor cells proliferate, fully differentiated cells exit the cell cycle. How cell identity and cell cycle state are coordinated during this process is still poorly understood. The Drosophila testis niche supports germline stem cells and somatic cyst stem cells (CySCs), which are the only proliferating somatic cells in the testis. CySCs give rise to post-mitotic cyst cells and therefore provide a tractable model to ask how stem cell identity is linked to proliferation. We show that the G1/S cyclin, Cyclin E, is required for CySC self-renewal; however, its canonical transcriptional regulator, a complex of the E2f1 and Dp transcription factors is dispensable for self-renewal and cell cycle progression. Nevertheless, we demonstrate that E2f1/Dp activity must be silenced to allow CySCs to differentiate. We show that E2f1/Dp activity inhibits the expression of genes important for mitochondrial activity. Furthermore, promoting mitochondrial activity or biogenesis is sufficient to rescue the differentiation of CySCs with ectopic E2f1/Dp activity but not their exit from the cell cycle. Our findings together indicate that E2f1/Dp coordinates cell cycle progression with stem cell identity by regulating the metabolic state of CySCs.

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Let-7 regulates cell cycle dynamics in the developing cerebral cortex and retina

Scientific Reports ◽

10.1038/s41598-019-51703-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Corinne L. A. Fairchild ◽

Simranjeet K. Cheema ◽

Joanna Wong ◽

Keiko Hino ◽

Sergi Simó ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Fate ◽

Cell Cycle Progression ◽

Developmental Time ◽

Neural Progenitors ◽

Cycle Progression ◽

Cell Fate Decisions ◽

Cell Cycle Dynamics

Abstract In the neural progenitors of the developing central nervous system (CNS), cell proliferation is tightly controlled and coordinated with cell fate decisions. Progenitors divide rapidly during early development and their cell cycle lengthens progressively as development advances to eventually give rise to a tissue of the correct size and cellular composition. However, our understanding of the molecules linking cell cycle progression to developmental time is incomplete. Here, we show that the microRNA (miRNA) let-7 accumulates in neural progenitors over time throughout the developing CNS. Intriguingly, we find that the level and activity of let-7 oscillate as neural progenitors progress through the cell cycle by in situ hybridization and fluorescent miRNA sensor analyses. We also show that let-7 mediates cell cycle dynamics: increasing the level of let-7 promotes cell cycle exit and lengthens the S/G2 phase of the cell cycle, while let-7 knock down shortens the cell cycle in neural progenitors. Together, our findings suggest that let-7 may link cell proliferation to developmental time and regulate the progressive cell cycle lengthening that occurs during development.

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