Essays in biochemistry最新文献

Among the ubiquitin-like superfamily, small ubiquitin-like modifiers (SUMOs) are the most well-understood. However, in comparison with the prototypical small modifier ubiquitin, our understanding of the SUMO system lags. SUMOylation is often characterised as 'simple' in comparison with ubiquitination, with fewer SUMO-specific writers, readers and erasers compared with the ubiquitin machinery. A key divergence between ubiquitin and SUMO is that the SUMOylation system utilises a group of related SUMOs (SUMO1- 5), each possessing distinct functions. SUMO paralogs share conjugation, recognition and deconjugation machinery, yet signalling can employ each to perform specific cellular functions. This illustrates a complex layer of molecular discrimination that is far from simple. The repair of DNA double-stranded breaks (DSBs) - highly toxic DNA lesions generated from both endogenous and external sources - serves as a fascinating exemplar of specificity in SUMO signalling. This review focuses on how signalling specificity is achieved during SUMO-DSB repair. Examples of how different branches of SUMO signalling can direct discrete DSB-repair outcomes through modulation of key repair factors, including the RAP80-BRCA1-A complex, RNF168 and CtIP, are described in further detail.

Protein quality control (PQC) systems are crucial for maintaining cellular proteostasis, particularly under stress that promotes misfolded protein accumulation. A central component of this response is the assembly of stress granules (SGs), cytoplasmic condensates of RNA and proteins that temporarily stall translation. Aberrant SG dynamics, often linked to mutations in SG proteins, contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), where persistent protein aggregates are hallmarks. This review examines the emerging role of the ubiquitin-like modifier NEDD8 and its deconjugating enzyme NEDP1 in regulating SG homeostasis. Recent studies identify NEDP1 as a critical factor controlling SG clearance. Inhibition of NEDP1 enhances SG turnover, prevents pathological solidification, and promotes the disassembly of toxic aggregates through hyper-NEDDylation of PARP1, a DNA repair enzyme that also governs SG dynamics. Unlike broad-spectrum PARP1 inhibitors, which can impair DNA repair and cause cytotoxicity, NEDP1 inhibition offers a stress-specific approach that preserves normal cellular functions. Encouragingly, NEDP1 inhibition effectively causes aggregate elimination in ALS patient-derived fibroblasts and restores motility in Caenorhabditis elegans disease models. Altogether, these findings highlight NEDP1 as a key regulator of SG regulation and a promising therapeutic target for ALS and related neurodegenerative disorders.

Cancer metastasis is one of the hallmarks of cancer. This multistep process involves a cascade of alterations at the cellular and molecular level, including the epithelial-to-mesenchymal transition (EMT), invasion, migration, extracellular matrix (ECM) degradation, angiogenesis, and colonization. Expression level of critical factors associated with these processes is altered at the post-translational level through ubiquitination. Therefore, E3 ubiquitin ligases, components of the ubiquitin-mediated proteasome system, play a crucial role in controlling each step of metastasis by promoting the ubiquitination of several important factors. In this review, we have summarized the importance of E3 ligase in metastasis. Several E3 ligases act as promoters, while others act as repressors of metastasis. This article focuses on the potential role of E3 ubiquitin ligases in cancer metastasis and reveals their molecular function and targets, which are crucial for therapeutic interventions in anti-cancer therapies. Further, we covered the development of small molecule inhibitors and proteolysis-targeting chimeras to target E3 ubiquitin ligases involved in promoting metastasis for therapeutic intervention. Despite tremendous advancements, there are still many unanswered questions, especially regarding the complete characterization of the diverse range of E3 ligase functions and the conversion of preclinical discoveries into successful clinical treatments. In addition, future directions are concentrated on using technologies to develop highly specific therapeutic interventions and exploring their potential in combination with other treatment modalities, including immunotherapy, to ultimately overcome the challenges of cancer metastasis.

Mental health disorder (MHD) incidence rates continue to rise, contributing significantly to the global disease burden. While their aetiology was once thought to be strictly genetic or environmental, the study of epigenetics has reshaped our understanding of their underlying mechanisms. Environmental exposures are understood as key players in the development of MHDs. Growing research has elucidated the critical role of environmental chemical exposures-particularly through endocrine-disrupting chemicals and heavy metals-in influencing MHD incidence through epigenetic mechanisms (i.e. DNA methylation, histone modification and non-coding RNA action). A key breakthrough in this field is the recognition that epigenetic modifications are not necessarily permanent. By exploiting the potential reversibility of DNA methylation and histone modification, new avenues for therapeutic interventions open, in which normal gene function could be restored. Understanding and harnessing epigenetic reversibility not only provides hope for novel and personalized treatment strategies but also underscores the importance of environmental protection policies in mental health prevention.

Ubiquitin (Ub) and Ub-like (Ubl) signaling processes regulate broad aspects of eukaryotic cellular biology. Conserved sets of enzymes control the covalent attachment of Ub/Ubl onto proteins, and disruption of these highly regulated processes contributes to diseases including cancer and neurodegeneration. Aspects of Ub/Ubl signaling are central to the innate immune response to infectious pathogens. As such, pathogens such as viruses and bacteria have evolved sophisticated mechanisms to hijack and dysregulate the homeostasis of Ub/Ubl signaling. Pathogenic manipulation of the host Ub system is well studied, with multiple classes of secreted bacterial effector proteins discovered that regulate either Ub itself or the enzymes required for substrate ubiquitylation. While much less is known about the control of host Ubl signaling processes by pathogens, recent discoveries indicate that they, too, are hijacked during infection. The number of Ubl manipulators secreted by bacterial pathogens is likely to increase in the coming years as methods to identify and characterize bacterial effectors advance. This review highlights the current knowledge on bacterial manipulation of Ubl signaling, including SUMO, NEDD8, ISG15, UFM1, FAT10, and LC3.

Alzheimer's disease (AD) is a neurodegenerative disease, representing the seventh cause of death worldwide and the first cause of dementia. Several pathogenic mechanisms have been connected to this pathology, including protein aggregation, oxidative stress, metabolic dysfunction, mitochondrial dysfunction, neuroinflammation, synaptic dysfunction, and cell death. The etiology of AD is multifactorial, suggesting that, in addition to a genetic component, the environment may strongly influence its onset and progression. Exposure to heavy metals, such as lead, cadmium, mercury, and arsenic (As), is known to be associated with AD, with As showing one of the strongest correlations, in relation to the epigenetic changes. The World Health Organization (WHO) set a very low limit for its concentration to 10 μg/l in drinking water. The possibility that As may induce epigenetic effects is a recent hypothesis. Evidence, so far, suggests that As may induce DNA hypomethylation in the brain, by mechanisms not yet completely disclosed. This minireview aims to provide evidence to support the role of As exposure in AD, maintaining a focus on oxidative stress and ferroptosis, with a perspective on DNA methylation.

Following a variety of early environmental experiences and exposures, epigenetic modifications such as DNA methylation are proposed as candidate mechanisms that contribute to health and disease across the lifespan. Epigenetic clocks are a type of aging biomarker that can offer insight into age-related changes associated with early environmental exposures. This review provides a brief overview of epigenetic clocks that are readily available for use with perinatal and/or pediatric samples, as well as highlights some recent research that has studied the associations between early environmental chemical exposures and epigenetic aging rates. Broadly, the easily accessible epigenetic clocks can be categorized as chronological age estimators and gestational age estimators, but some clocks were developed for use with specific tissues and/or age groups. Previous environmental epidemiology studies have shown that early environmental exposures such as air pollutants and endocrine-disrupting chemicals are associated with altered epigenetic aging rates in perinatal and pediatric populations. However, more research is needed that examines how factors such as exposure level, timing of exposure, and sex may affect the direction and magnitude of associations. This review concludes with some recommendations and future directions for the use of epigenetic clocks in environmental epigenetics. Overall, epigenetic clocks are promising, non-causal biomarkers of early exposures that can be examined in relation to environmental chemicals, health and disease outcomes, and as biological mediators. Future research could help determine whether these clocks hold promise as informative biomarkers that reflect developmental epigenotoxicity following early exposure to environmental chemicals.

Two epigenetically labile subsets of genes that link embryonic environmental exposures with adult disease susceptibility are those that are imprinted and those with metastable epialleles. The expression of genes with metastable epialleles, like the agouti gene in Agouti viable yellow (Avy) mice, is highly variable between individuals but uniform in tissues within an individual. We used the Avy mouse to demonstrate that exposure to nutritional supplements, chemical toxicants, and low-dose ionizing radiation during embryogenesis alters adult disease susceptibility by modifying the epigenome. Genomic imprinting is a unique species-dependent epigenetic form of gene regulation that evolved approximately 150 million years ago in a common ancestor to Therian mammals. It resulted in monoallelic parent-of-origin-dependent gene silencing. Thus, imprinted genes are functionally haploid disease susceptibility loci, since only a single genetic or epigenetic event is required to alter their function. Expression of imprinted genes in the human genome is regulated by hemi-methylated imprint control regions (ICRs) in the human imprintome. Furthermore, human imprintome ICRs associated with chronic diseases (e.g., cancer, diabetes, and obesity) and behavioral disorders (e.g., autism, bipolar disorder, psychopathy, and schizophrenia) can now be identified with the use of cells from peripheral samples and the human imprintome array. The importance of metastable epialleles and imprinted genes in the etiology of environmentally induced human chronic diseases is discussed in this review.

Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. Recent studies have implicated a novel link between exposures to endocrine-disrupting chemicals (EDCs) and CVD. EDCs are a group of persistent compounds that can interfere with the body's natural hormonal processes, posing significant risks to both environment and human health. However, the impact and underlying mechanisms of EDC exposures on atherosclerosis are poorly understood, making it difficult to conduct rational exposure assessments. EDCs can affect CVD risk through multiple mechanisms, and epigenetic mechanisms are key mechanisms for environmental factor-elicited chronic diseases. Further, EDC-elicited epigenetic alterations may not only affect atherosclerosis development in exposed individuals but also lead to increased CVD risk in their descendants. In this review, we mainly focus on the current understanding of EDC-mediated epigenetic regulation and epigenetic inheritance of CVD. In addition, EDC-carrying microplastics and nanoplastics have emerged as significant environmental pollutants, and humans are ubiquitously exposed to these particles. We also discuss the potential impact of co-exposures of EDCs and small plastic particles on atherosclerosis and CVD.

SUMOylation, a protein post-translational modification (PTM) involving the covalent attachment of small ubiquitin-like modifier (SUMO), regulates a wide range of cellular processes. The key hallmark of SUMO that distinguishes it from ubiquitin is the hydrophobic groove that binds short linear motifs known as SUMO-interacting motifs (SIMs), which are found across a broad spectrum of partners, including SUMO E3 ligases and downstream effector proteins such as transcription factors, DNA-repair proteins, ubiquitin E3 ligases and cell-signalling components. In addition, various effectors interacting in a SIM-independent manner have been reported. In this review, we summarise the current understanding of non-covalent SUMO interactions mediated by SIMs and other, alternative SUMO-binding elements. Focusing on the evolution and structural basis of these interactions, we discuss the methodological approaches used in the field, outline emerging mechanisms and concepts and highlight key open questions.