BioEssays

Cobley, James N.

doi: 10.1002/bies.202200248pmid: 37147790

A single protein molecule with one or more cysteine residues can occupy a plurality of unique residue and oxidation‐chemotype specified proteoforms that I term oxiforms. In binary reduced or oxidised terms, one molecule with three cysteines will adopt one of eight unique oxiforms. Residue‐defined sulfur chemistry endows specific oxiforms with distinct functionally‐relevant biophysical properties (e.g., steric effects). Their emergent complexity means a functionally‐relevant effect may only manifest when multiple cysteines are oxidised. Like how mixing colours makes new shades, combining discrete redox chemistries—colours—can create a kaleidoscope of oxiform hues. The sheer diversity of oxiforms co‐existing within the human body provides a biological basis for redox heterogeneity. Of evolutionary significance, oxiforms may enable individual cells to mount a broad spectrum of responses to the same stimulus. Their biological significance, however plausible, is speculative because protein‐specific oxiforms remain essentially unexplored. Excitingly, pioneering new techniques can push the field into uncharted territory by quantifying oxiforms. The oxiform concept can advance our understanding of redox‐regulation in health and disease.

Ryazansky, Sergei; Akulenko, Natalia

doi: 10.1002/bies.202200220pmid: 37142884

miRNA‐mediated gene repression and ubiquitin‐dependent processes are among the oldest and most versatile mechanisms that control multiple molecular pathways, rather than just protein turnover. These systems were discovered decades ago and have become among the most studied. All systems within cells are interconnected, and these two are no exception: the plethora of studies have demonstrated that the activity of the miRNAs system depends on players of the ubiquitin‐centered universe of processes, and vice versa. This review focuses on recent progress that highlights that very similar mechanisms of regulation of miRNAs by ubiquitin‐related processes are likely to be found in distantly related species, including animals, plants, and viruses. Most of them occur through the ubiquitination of Argonaute proteins, but some of the other miRNA system factors are also regulated. This suggests that their regulatory relationships are either ancient evolutionary acquisitions or have arisen independently in different kingdoms.

Lloyd, Stephanie; Lutz, Pierre‐Eric; Bonventre, Chani

doi: 10.1002/bies.202300019pmid: 37166059

Just over 20 years ago, molecular biologists Leonie Ringrose and Renato Paro published an article with a provocative title, “Remembering Silence”, in BioEssays. The article focused on how epigenetic elements could return to their silent state, operationally defined as their epigenetic status before their modulation by experimental or environmental factors. Though Ringrose and Paro's article was on fruit flies and factors affecting embryological growth, the article asked a question of considerable importance to rapidly expanding research in neuroepigenetics on the correlation between trauma and neuropsychiatric risk: If you experience a traumatic event and, as a result, acquire an epigenetic trait that is considered pathological, can you free yourself of that trait? Ultimately, we are interested in how a return to silence is envisioned in neuroepigenetics research, how interventions purported to bring about that silence might function, and what this might mean for people who live in the aftermath of trauma.

Varshavsky, Alexander; Lewis, Kim; Chen, Shun‐Jia

doi: 10.1002/bies.202300051pmid: 37166062

Despite advances in treatments over the last decades, a uniformly reliable and free of side effects therapy of human cancers remains to be achieved. During chromosome replication, a premature halt of two converging DNA replication forks would cause incomplete replication and a cytotoxic chromosome nondisjunction during mitosis. In contrast to normal cells, most cancer cells bear numerous DNA deletions. A homozygous deletion permanently marks a cell and its descendants. Here, we propose an approach to cancer therapy in which a pair of sequence‐specific roadblocks is placed solely at two cancer‐confined deletion sites that are located ahead of two converging replication forks. We describe this method, termed “replication blocks specific for deletions” (RBSD), and another deletions‐based approach as well. RBSD can be expanded by placing pairs of replication roadblocks on several different chromosomes. The resulting simultaneous nondisjunctions of these chromosomes in cancer cells would further increase the cancer‐specific toxicity of RBSD.

Wilkens, Stephan; Khan, Md. Murad; Knight, Kassidy; Oot, Rebecca A.

doi: 10.1002/bies.202200251pmid: 37183929

Vacuolar ATPases (V‐ATPases, V1Vo‐ATPases) are rotary motor proton pumps that acidify intracellular compartments, and, when localized to the plasma membrane, the extracellular space. V‐ATPase is regulated by a unique process referred to as reversible disassembly, wherein V1‐ATPase disengages from Vo proton channel in response to diverse environmental signals. Whereas the disassembly step of this process is ATP dependent, the (re)assembly step is not, but requires the action of a heterotrimeric chaperone referred to as the RAVE complex. Recently, an alternative pathway of holoenzyme disassembly was discovered that involves binding of Oxidation Resistance 1 (Oxr1p), a poorly characterized protein implicated in oxidative stress response. Unlike conventional reversible disassembly, which depends on enzyme activity, Oxr1p induced dissociation can occur in absence of ATP. Yeast Oxr1p belongs to the family of TLDc domain containing proteins that are conserved from yeast to mammals, and have been implicated in V‐ATPase function in a variety of tissues. This brief perspective summarizes what we know about the molecular mechanisms governing both reversible (ATP dependent) and Oxr1p driven (ATP independent) V‐ATPase dissociation into autoinhibited V1 and Vo subcomplexes.

Fabre, Alexandre; Fabre, Anne; Bon, Céline; Guerry, Paul; Segurel, Laure

doi: 10.1002/bies.202200243pmid: 37075758

Lactase persistence/persistent (LP), the ability to express the lactase enzyme in adults, is one of the most strongly selected phenotypes in humans. It is encoded by at least five genetic variants that have rapidly become widespread in various human populations. The underlying selective mechanism is not clear however, because dairy products in general are well tolerated in adults, even by lactase non‐persistence/persistent (LNP) individuals. Cultural adaptations to milk consumption, notably fermentation and transformation, which can provide most of the energy (protein, fat) to both LP and LNP individuals without any associated cost seem to have been common in ancient societies. Here, we propose that selection for LP occurred through increased glucose/galactose (energy) from fresh milk intake in early childhood, a crucial period for growth. At the age of weaning indeed, lactase activity has already begun to decline in LNP individuals so the gain in energy from fresh milk by LP children represents a major fitness increase.

Arkhipova, Irina R.; Yushenova, Irina A.; Rodriguez, Fernando

doi: 10.1002/bies.202200232pmid: 37339822

DNA methylation constitutes one of the pillars of epigenetics, relying on covalent bonds for addition and/or removal of chemically distinct marks within the major groove of the double helix. DNA methyltransferases, enzymes which introduce methyl marks, initially evolved in prokaryotes as components of restriction‐modification systems protecting host genomes from bacteriophages and other invading foreign DNA. In early eukaryotic evolution, DNA methyltransferases were horizontally transferred from bacteria into eukaryotes several times and independently co‐opted into epigenetic regulatory systems, primarily via establishing connections with the chromatin environment. While C5‐methylcytosine is the cornerstone of plant and animal epigenetics and has been investigated in much detail, the epigenetic role of other methylated bases is less clear. The recent addition of N4‐methylcytosine of bacterial origin as a metazoan DNA modification highlights the prerequisites for foreign gene co‐option into the host regulatory networks, and challenges the existing paradigms concerning the origin and evolution of eukaryotic regulatory systems.

Tansey, William P.

doi: 10.1002/bies.202300064pmid: 37178253

doi: 10.1002/bies.202370061pmid: N/A

doi: 10.1002/bies.202370062pmid: N/A