Nucleolar Signaling Determines Cell Fate: The RP-Mdm2-p53 Axis Fine-Tunes Cellular Homeostasis

Numb is a protein that in Drosophila determines cell fate as a result of its asymmetric partitioning at mitosis. The function of Numb has been linked to its ability to bind and to biologically antagonize Notch, a membrane receptor that also specifies cell fate. The biochemical mechanisms underlying the action of Numb, however, are still largely unknown. The wide pattern of expression of Numb suggests a general function in cellular homeostasis that could be additional to, or part of, its action in fate determination. Such a function could be endocytosis, as suggested by the interaction of Numb with Eps15, a component of the endocytic machinery. Here, we demonstrate that Numb is an endocytic protein. We found that Numb localizes to endocytic organelles and is cotrafficked with internalizing receptors. Moreover, it associates with the appendage domain of α adaptin, a subunit of AP2, a major component of clathrin-coated pits. Finally, fragments of Numb act as dominant negatives on both constitutive and ligand-regulated receptor-mediated internalization, suggesting a general role for Numb in the endocytic process.

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Autophagic Organelles in DNA Damage Response

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.668735 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jeongha Kim ◽

Sungmin Lee ◽

Hyunwoo Kim ◽

Haksoo Lee ◽

Ki Moon Seong ◽

...

Keyword(s):

Dna Damage ◽

Cell Fate ◽

Dna Damage Response ◽

Cellular Homeostasis ◽

Dna Damaging Agents ◽

Anti Cancer ◽

Damage Response ◽

Cargo Proteins ◽

Cellular Stresses ◽

Key Events

Autophagy is an important subcellular event engaged in the maintenance of cellular homeostasis via the degradation of cargo proteins and malfunctioning organelles. In response to cellular stresses, like nutrient deprivation, infection, and DNA damaging agents, autophagy is activated to reduce the damage and restore cellular homeostasis. One of the responses to cellular stresses is the DNA damage response (DDR), the intracellular pathway that senses and repairs damaged DNA. Proper regulation of these pathways is crucial for preventing diseases. The involvement of autophagy in the repair and elimination of DNA aberrations is essential for cell survival and recovery to normal conditions, highlighting the importance of autophagy in the resolution of cell fate. In this review, we summarized the latest information about autophagic recycling of mitochondria, endoplasmic reticulum (ER), and ribosomes (called mitophagy, ER-phagy, and ribophagy, respectively) in response to DNA damage. In addition, we have described the key events necessary for a comprehensive understanding of autophagy signaling networks. Finally, we have highlighted the importance of the autophagy activated by DDR and appropriate regulation of autophagic organelles, suggesting insights for future studies. Especially, DDR from DNA damaging agents including ionizing radiation (IR) or anti-cancer drugs, induces damage to subcellular organelles and autophagy is the key mechanism for removing impaired organelles.

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Mitochondrial hyperfusion: a friend or a foe

Biochemical Society Transactions ◽

10.1042/bst20190987 ◽

2020 ◽

Vol 48 (2) ◽

pp. 631-644 ◽

Cited By ~ 3

Author(s):

Rajdeep Das ◽

Oishee Chakrabarti

Keyword(s):

Negative Impact ◽

Cellular Stress ◽

Cellular Homeostasis ◽

Mitochondrial Population

The cellular mitochondrial population undergoes repeated cycles of fission and fusion to maintain its integrity, as well as overall cellular homeostasis. While equilibrium usually exists between the fission–fusion dynamics, their rates are influenced by organellar and cellular metabolic and pathogenic conditions. Under conditions of cellular stress, there is a disruption of this fission and fusion balance and mitochondria undergo either increased fusion, forming a hyperfused meshwork or excessive fission to counteract stress and remove damaged mitochondria via mitophagy. While some previous reports suggest that hyperfusion is initiated to ameliorate cellular stress, recent studies show its negative impact on cellular health in disease conditions. The exact mechanism of mitochondrial hyperfusion and its role in maintaining cellular health and homeostasis, however, remain unclear. In this review, we aim to highlight the different aspects of mitochondrial hyperfusion in either promoting or mitigating stress and also its role in immunity and diseases.

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Centrosome Aurora A gradient ensures single polarity axis in C. elegans embryos

Biochemical Society Transactions ◽

10.1042/bst20200298 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1243-1253 ◽

Cited By ~ 1

Author(s):

Sukriti Kapoor ◽

Sachin Kotak

Keyword(s):

Symmetry Breaking ◽

Cell Fate ◽

Cell Cortex ◽

Axis Formation ◽

Aurora A Kinase ◽

Aurora A ◽

C Elegans ◽

Cell Embryo ◽

Polarity Establishment

Cellular asymmetries are vital for generating cell fate diversity during development and in stem cells. In the newly fertilized Caenorhabditis elegans embryo, centrosomes are responsible for polarity establishment, i.e. anterior–posterior body axis formation. The signal for polarity originates from the centrosomes and is transmitted to the cell cortex, where it disassembles the actomyosin network. This event leads to symmetry breaking and the establishment of distinct domains of evolutionarily conserved PAR proteins. However, the identity of an essential component that localizes to the centrosomes and promotes symmetry breaking was unknown. Recent work has uncovered that the loss of Aurora A kinase (AIR-1 in C. elegans and hereafter referred to as Aurora A) in the one-cell embryo disrupts stereotypical actomyosin-based cortical flows that occur at the time of polarity establishment. This misregulation of actomyosin flow dynamics results in the occurrence of two polarity axes. Notably, the role of Aurora A in ensuring a single polarity axis is independent of its well-established function in centrosome maturation. The mechanism by which Aurora A directs symmetry breaking is likely through direct regulation of Rho-dependent contractility. In this mini-review, we will discuss the unconventional role of Aurora A kinase in polarity establishment in C. elegans embryos and propose a refined model of centrosome-dependent symmetry breaking.

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Centromere assembly and non-random sister chromatid segregation in stem cells

Essays in Biochemistry ◽

10.1042/ebc20190066 ◽

2020 ◽

Vol 64 (2) ◽

pp. 223-232 ◽

Cited By ~ 1

Author(s):

Ben L. Carty ◽

Elaine M. Dunleavy

Keyword(s):

Stem Cells ◽

Cell Division ◽

Cell Fate ◽

Sister Chromatid ◽

Asymmetric Cell Division ◽

Protein A ◽

Germline Stem Cells ◽

Sister Chromatids ◽

Centromere Protein A ◽

Oocyte Meiosis

Abstract Asymmetric cell division (ACD) produces daughter cells with separate distinct cell fates and is critical for the development and regulation of multicellular organisms. Epigenetic mechanisms are key players in cell fate determination. Centromeres, epigenetically specified loci defined by the presence of the histone H3-variant, centromere protein A (CENP-A), are essential for chromosome segregation at cell division. ACDs in stem cells and in oocyte meiosis have been proposed to be reliant on centromere integrity for the regulation of the non-random segregation of chromosomes. It has recently been shown that CENP-A is asymmetrically distributed between the centromeres of sister chromatids in male and female Drosophila germline stem cells (GSCs), with more CENP-A on sister chromatids to be segregated to the GSC. This imbalance in centromere strength correlates with the temporal and asymmetric assembly of the mitotic spindle and potentially orientates the cell to allow for biased sister chromatid retention in stem cells. In this essay, we discuss the recent evidence for asymmetric sister centromeres in stem cells. Thereafter, we discuss mechanistic avenues to establish this sister centromere asymmetry and how it ultimately might influence cell fate.

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