BioEssays

Sterling, Noelle A.; Cho, Seo‐Hee; Kim, Seonhee

doi: 10.1002/bies.202300245pmid: 38778437

Entosis, a form of cell cannibalism, is a newly discovered pathogenic mechanism leading to the development of small brains, termed microcephaly, in which P53 activation was found to play a major role. Microcephaly with entosis, found in Pals1 mutant mice, displays P53 activation that promotes entosis and apoptotic cell death. This previously unappreciated pathogenic mechanism represents a novel cellular dynamic in dividing cortical progenitors which is responsible for cell loss. To date, various recent models of microcephaly have bolstered the importance of P53 activation in cell death leading to microcephaly. P53 activation caused by mitotic delay or DNA damage manifests apoptotic cell death which can be suppressed by P53 removal in these animal models. Such genetic studies attest P53 activation as quality control meant to eliminate genomically unfit cells with minimal involvement in the actual function of microcephaly associated genes. In this review, we summarize the known role of P53 activation in a variety of microcephaly models and introduce a novel mechanism wherein entotic cell cannibalism in neural progenitors is triggered by P53 activation.

Kuna, Marija; Soares, Michael J.

doi: 10.1002/bies.202300118pmid: 38922923

The biology of trophoblast cell lineage development and placentation is characterized by the involvement of several known transcription factors. Central to the action of a subset of these transcriptional regulators is CBP‐p300 interacting transactivator with Glu/Asp‐rich carboxy‐terminal domain 2 (CITED2). CITED2 acts as a coregulator modulating transcription factor activities and affecting placental development and adaptations to physiological stressors. These actions of CITED2 on the trophoblast cell lineage and placentation are conserved across the mouse, rat, and human. Thus, aspects of CITED2 biology in hemochorial placentation can be effectively modeled in the mouse and rat. In this review, we present information on the conserved role of CITED2 in the biology of placentation and discuss the use of CITED2 as a tool to discover new insights into regulatory mechanisms controlling placental development.

Técher, Hervé

doi: 10.1002/bies.202400066pmid: 38837436

The Three Prime Repair Exonuclease 1 (TREX1) has been implicated in several pathologies characterized by chronic and inborn inflammation. Aberrant innate immunity caused by DNA sensing through the cGAS‐STING pathway has been proposed to play a major role in the etiology of these interferonopathies. However, the molecular source of this DNA sensing and the possible involvement of TREX1 in genome (in)stability remains poorly understood. Recent findings reignite the debate about the cellular functions performed by TREX1 nuclease, notably in chromosome biology and stability. Here I put into perspective recent findings that suggest that TREX1 is at the crossroads of DNA damage response and inflammation in different pathological contexts.

Belaadi, Nejma; Guilluy, Christophe

doi: 10.1002/bies.202400034pmid: 38798157

Sad1 and UNC84 (SUN) and Klarsicht, ANC‐1, and Syne homology (KASH) proteins interact at the nuclear periphery to form the linker of nucleoskeleton and cytoskeleton (LINC) complex, spanning the nuclear envelope (NE) and connecting the cytoskeleton with the nuclear interior. It is now well‐documented that several cellular functions depend on LINC complex formation, including cell differentiation and migration. Intriguingly, recent studies suggest that SUN proteins participate in cellular processes where their association with KASH proteins may not be required. Building on this recent research, we elaborate on the hypothesis that SUN proteins may perform LINC‐independent functions and discuss the modalities that may allow SUN proteins to function at the INM when they are not forming LINC complex.

Hanada, Kentaro

doi: 10.1002/bies.202400045pmid: 38932642

Various lipid transfer proteins (LTPs) mediate the inter‐organelle transport of lipids. By working at membrane contact zones between donor and acceptor organelles, LTPs achieve rapid and accurate inter‐organelle transfer of lipids. This article will describe the emerging paradigm that the action of LTPs at organelle contact zones generates metabolic channeling events in lipid metabolism, mainly referring to how ceramide synthesized in the endoplasmic reticulum is preferentially metabolized to sphingomyelin in the distal Golgi region, how cholesterol and phospholipids receive specific metabolic reactions in mitochondria, and how the hijacking of host LTPs by intracellular pathogens may generate new channeling‐like events. In addition, the article will discuss how the function of LTPs is regulated, exemplified by a few representative LTP systems, and will briefly touch on experiments that will be necessary to establish the paradigm that LTP‐mediated inter‐organelle transport of lipids is one of the mechanisms of compartmentalization‐based metabolic channeling events.

doi: 10.1002/bies.202470012pmid: N/A

Bearne, Stephen L.

doi: 10.1002/bies.202400063pmid: 38975656

A host of metabolic enzymes reversibly self‐assemble to form membrane‐less, intracellular filaments under normal physiological conditions and in response to stress. Often, these enzymes reside at metabolic control points, suggesting that filament formation affords an additional regulatory mechanism. Examples include cytidine‐5′‐triphosphate (CTP) synthase (CTPS), which catalyzes the rate‐limiting step for the de novo biosynthesis of CTP; inosine‐5′‐monophosphate dehydrogenase (IMPDH), which controls biosynthetic access to guanosine‐5′‐triphosphate (GTP); and ∆1‐pyrroline‐5‐carboxylate (P5C) synthase (P5CS) that catalyzes the formation of P5C, which links the Krebs cycle, urea cycle, and proline metabolism. Intriguingly, CTPS can exist in co‐assemblies with IMPDH or P5CS. Since GTP is an allosteric activator of CTPS, the association of CTPS and IMPDH filaments accords with the need to coordinate pyrimidine and purine biosynthesis. Herein, a hypothesis is presented furnishing a biochemical connection underlying co‐assembly of CTPS and P5CS filaments – potent inhibition of CTPS by glutamate γ‐semialdehyde, the open‐chain form of P5C.

Dharan, Raviv; Sorkin, Raya

doi: 10.1002/bies.202400051pmid: 38922978

The transient cellular organelles known as migrasomes, which form during cell migration along retraction fibers, have emerged as a crutial factor in various fundamental cellular processes and pathologies. These membrane vesicles originate from local membrane swellings, encapsulate specific cytoplasmic content, and are eventually released to the extracellular environment or taken up by recipient cells. Migrasome biogenesis entails a sequential membrane remodeling process involving a complex interplay between various molecular factors such as tetraspanin proteins, and mechanical properties like membrane tension and bending rigidity. In this review, we summarize recent studies exploring the mechanism of migrasome formation. We emphasize how physical forces, together with molecular factors, shape migrasome biogenesis, and detail the involvement of migrasomes in various cellular processes and pathologies. A comprehensive understanding of the exact mechanism underlying migrasome formation and the identification of key molecules involved hold promise for advancing their therapeutic and diagnostic applications.

Uboveja, Apoorva; Aird, Katherine M.

doi: 10.1002/bies.202300166pmid: 38873912

Ovarian cancer is the most lethal gynecological malignancy and is often associated with both DNA repair deficiency and extensive metabolic reprogramming. While still emerging, the interplay between these pathways can affect ovarian cancer phenotypes, including therapeutic resistance to the DNA damaging agents that are standard‐of‐care for this tumor type. In this review, we will discuss what is currently known about cellular metabolic rewiring in ovarian cancer that may impact DNA damage and repair in addition to highlighting how specific DNA repair proteins also promote metabolic changes. We will also discuss relevant data from other cancers that could be used to inform ovarian cancer therapeutic strategies. Changes in the choice of DNA repair mechanism adopted by ovarian cancer are a major factor in promoting therapeutic resistance. Therefore, the impact of metabolic reprogramming on DNA repair mechanisms in ovarian cancer has major clinical implications for targeted combination therapies for the treatment of this devastating disease.

doi: 10.1002/bies.202470013pmid: N/A