Histones are essential for maintaining chromatin structure and function. Histone mutations lead to changes in chromatin compaction, gene expression, and the recruitment of DNA repair proteins to the DNA lesion. These disruptions can impair critical DNA repair pathways, such as homologous recombination and non-homologous end joining, resulting in increased genomic instability, which promotes an environment favorable to tumor development and progression. Understanding these mechanisms underscores the potential of targeting DNA repair pathways in cancers harboring mutated histones, offering novel therapeutic strategies to exploit their inherent genomic instability for better treatment outcomes. Here, we examine how mutations in histone H3 disrupt normal chromatin function and DNA damage repair processes and how these mechanisms can be exploited for therapeutic interventions.
组蛋白对维持染色质结构和功能至关重要。组蛋白突变会导致染色质压实、基因表达和 DNA 修复蛋白被招募到 DNA 病变部位。这些破坏会损害关键的 DNA 修复途径,如同源重组和非同源末端连接,导致基因组不稳定性增加,从而形成有利于肿瘤发生和发展的环境。了解了这些机制后,我们就可以针对携带突变组蛋白的癌症中的DNA修复途径,提供新的治疗策略,利用其固有的基因组不稳定性获得更好的治疗效果。在这里,我们将研究组蛋白H3的突变如何破坏正常的染色质功能和DNA损伤修复过程,以及如何利用这些机制进行治疗干预。
{"title":"Histone H3 mutations and their impact on genome stability maintenance.","authors":"Lucas D Caeiro, Ramiro E Verdun, Lluis Morey","doi":"10.1042/BST20240177","DOIUrl":"https://doi.org/10.1042/BST20240177","url":null,"abstract":"<p><p>Histones are essential for maintaining chromatin structure and function. Histone mutations lead to changes in chromatin compaction, gene expression, and the recruitment of DNA repair proteins to the DNA lesion. These disruptions can impair critical DNA repair pathways, such as homologous recombination and non-homologous end joining, resulting in increased genomic instability, which promotes an environment favorable to tumor development and progression. Understanding these mechanisms underscores the potential of targeting DNA repair pathways in cancers harboring mutated histones, offering novel therapeutic strategies to exploit their inherent genomic instability for better treatment outcomes. Here, we examine how mutations in histone H3 disrupt normal chromatin function and DNA damage repair processes and how these mechanisms can be exploited for therapeutic interventions.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chromatin remodelling enzymes reposition nucleosomes throughout the genome to regulate the rate of transcription and other processes. These enzymes have been studied intensively since the 1990s, and yet the mechanism by which they operate has only very recently come into focus, following advances in cryoelectron microscopy and single-molecule biophysics. CHD4 is an essential and ubiquitous chromatin remodelling enzyme that until recently has received less attention than remodellers such as Snf2 and CHD1. Here we review what recent work in the field has taught us about how CHD4 reshapes the genome. Cryoelectron microscopy and single-molecule studies demonstrate that CHD4 shares a central remodelling mechanism with most other chromatin remodellers. At the same time, differences between CHD4 and other chromatin remodellers result from the actions of auxiliary domains that regulate remodeller activity by for example: (1) making differential interactions with nucleosomal epitopes such as the acidic patch and the N-terminal tail of histone H4, and (2) inducing the formation of distinct multi-protein remodelling complexes (e.g. NuRD vs ChAHP). Thus, although we have learned much about remodeller activity, there is still clearly much more waiting to be revealed.
{"title":"How does CHD4 slide nucleosomes?","authors":"Xavier J Reid, Yichen Zhong, Joel P Mackay","doi":"10.1042/BST20230070","DOIUrl":"https://doi.org/10.1042/BST20230070","url":null,"abstract":"<p><p>Chromatin remodelling enzymes reposition nucleosomes throughout the genome to regulate the rate of transcription and other processes. These enzymes have been studied intensively since the 1990s, and yet the mechanism by which they operate has only very recently come into focus, following advances in cryoelectron microscopy and single-molecule biophysics. CHD4 is an essential and ubiquitous chromatin remodelling enzyme that until recently has received less attention than remodellers such as Snf2 and CHD1. Here we review what recent work in the field has taught us about how CHD4 reshapes the genome. Cryoelectron microscopy and single-molecule studies demonstrate that CHD4 shares a central remodelling mechanism with most other chromatin remodellers. At the same time, differences between CHD4 and other chromatin remodellers result from the actions of auxiliary domains that regulate remodeller activity by for example: (1) making differential interactions with nucleosomal epitopes such as the acidic patch and the N-terminal tail of histone H4, and (2) inducing the formation of distinct multi-protein remodelling complexes (e.g. NuRD vs ChAHP). Thus, although we have learned much about remodeller activity, there is still clearly much more waiting to be revealed.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E3 ubiquitin ligases regulate the composition of the proteome. These enzymes mono- or poly-ubiquitinate their substrates, directly altering protein function or targeting proteins for degradation by the proteasome. In this review, we discuss the opposing roles of human E3 ligases as effectors and targets in the evolutionary battle between host and pathogen, specifically in the context of SARS-CoV-2 infection. Through complex effects on transcription, translation, and protein trafficking, human E3 ligases can either attenuate SARS-CoV-2 infection or become vulnerabilities that are exploited by the virus to suppress the host's antiviral defenses. For example, the human E3 ligase RNF185 regulates the stability of SARS-CoV-2 envelope protein through the ubiquitin-proteasome pathway, and depletion of RNF185 significantly increases SARS-CoV-2 viral titer (iScience (2023) 26, 106601). We highlight recent advances that identify functions for numerous human E3 ligases in the SARS-CoV-2 life cycle and we assess their potential as novel antiviral agents.
{"title":"Human E3 ubiquitin ligases: accelerators and brakes for SARS-CoV-2 infection.","authors":"Jesse Pellman, Anna Goldstein, Mikołaj Słabicki","doi":"10.1042/BST20230324","DOIUrl":"https://doi.org/10.1042/BST20230324","url":null,"abstract":"<p><p>E3 ubiquitin ligases regulate the composition of the proteome. These enzymes mono- or poly-ubiquitinate their substrates, directly altering protein function or targeting proteins for degradation by the proteasome. In this review, we discuss the opposing roles of human E3 ligases as effectors and targets in the evolutionary battle between host and pathogen, specifically in the context of SARS-CoV-2 infection. Through complex effects on transcription, translation, and protein trafficking, human E3 ligases can either attenuate SARS-CoV-2 infection or become vulnerabilities that are exploited by the virus to suppress the host's antiviral defenses. For example, the human E3 ligase RNF185 regulates the stability of SARS-CoV-2 envelope protein through the ubiquitin-proteasome pathway, and depletion of RNF185 significantly increases SARS-CoV-2 viral titer (iScience (2023) 26, 106601). We highlight recent advances that identify functions for numerous human E3 ligases in the SARS-CoV-2 life cycle and we assess their potential as novel antiviral agents.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amelia Bryers, Cheryl A Hawkes, Edward Parkin, Neil Dawson
Autism spectrum disorders (ASD) are a heterogenous set of syndromes characterised by social impairment and cognitive symptoms. Currently, there are limited treatment options available to help people with ASD manage their symptoms. Understanding the biological mechanisms that result in ASD diagnosis and symptomatology is an essential step in developing new interventional strategies. Human genetic studies have identified common gene variants of small effect and rare risk genes and copy number variants (CNVs) that substantially increase the risk of developing ASD. Reverse translational studies using rodent models based on these genetic variants provide new insight into the biological basis of ASD. Here we review recent findings from three ASD associated CNV mouse models (16p11.2, 2p16.3 and 22q11.2 deletion) that show behavioural and cognitive phenotypes relevant to ASD. These models have identified disturbed excitation-inhibition neurotransmitter balance, evidenced by dysfunctional glutamate and GABA signalling, as a key aetiological mechanism. These models also provide emerging evidence for serotoninergic neurotransmitter system dysfunction, although more work is needed to clarify the nature of this. At the brain network level, prefrontal cortex (PFC) dysfunctional connectivity is also evident across these models, supporting disturbed PFC function as a key nexus in ASD aetiology. Overall, published data highlight the utility and valuable insight gained into ASD aetiology from preclinical CNV mouse models. These have identified key aetiological mechanisms that represent putative novel therapeutic targets for the treatment of ASD symptoms, making them useful translational models for future drug discovery, development and validation.
{"title":"Progress towards understanding risk factor mechanisms in the development of autism spectrum disorders.","authors":"Amelia Bryers, Cheryl A Hawkes, Edward Parkin, Neil Dawson","doi":"10.1042/BST20231004","DOIUrl":"https://doi.org/10.1042/BST20231004","url":null,"abstract":"<p><p>Autism spectrum disorders (ASD) are a heterogenous set of syndromes characterised by social impairment and cognitive symptoms. Currently, there are limited treatment options available to help people with ASD manage their symptoms. Understanding the biological mechanisms that result in ASD diagnosis and symptomatology is an essential step in developing new interventional strategies. Human genetic studies have identified common gene variants of small effect and rare risk genes and copy number variants (CNVs) that substantially increase the risk of developing ASD. Reverse translational studies using rodent models based on these genetic variants provide new insight into the biological basis of ASD. Here we review recent findings from three ASD associated CNV mouse models (16p11.2, 2p16.3 and 22q11.2 deletion) that show behavioural and cognitive phenotypes relevant to ASD. These models have identified disturbed excitation-inhibition neurotransmitter balance, evidenced by dysfunctional glutamate and GABA signalling, as a key aetiological mechanism. These models also provide emerging evidence for serotoninergic neurotransmitter system dysfunction, although more work is needed to clarify the nature of this. At the brain network level, prefrontal cortex (PFC) dysfunctional connectivity is also evident across these models, supporting disturbed PFC function as a key nexus in ASD aetiology. Overall, published data highlight the utility and valuable insight gained into ASD aetiology from preclinical CNV mouse models. These have identified key aetiological mechanisms that represent putative novel therapeutic targets for the treatment of ASD symptoms, making them useful translational models for future drug discovery, development and validation.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Addison A Young, Holly E Bohlin, Jackson R Pierce, Kyle A Cottrell
Immunotherapy has emerged as a therapeutic option for many cancers. For some tumors, immune checkpoint inhibitors show great efficacy in promoting anti-tumor immunity. However, not all tumors respond to immunotherapies. These tumors often exhibit reduced inflammation and are resistant to checkpoint inhibitors. Therapies that turn these 'cold' tumors 'hot' could improve the efficacy and applicability of checkpoint inhibitors, and in some cases may be sufficient on their own to promote anti-tumor immunity. One strategy to accomplish this goal is to activate innate immunity pathways within the tumor. Here we describe how this can be accomplished by activating double-stranded RNA (dsRNA) sensors. These sensors evolved to detect and respond to dsRNAs arising from viral infection but can also be activated by endogenous dsRNAs. A set of proteins, referred to as suppressors of dsRNA sensing, are responsible for preventing sensing 'self' dsRNA and activating innate immunity pathways. The mechanism of action of these suppressors falls into three categories: (1) Suppressors that affect mature RNAs through editing, degradation, restructuring, or binding. (2) Suppressors that affect RNA processing. (3) Suppressors that affect RNA expression. In this review we highlight suppressors that function through each mechanism, provide examples of the effects of disrupting those suppressors in cancer cell lines and tumors, and discuss the therapeutic potential of targeting these proteins and pathways.
{"title":"Suppression of double-stranded RNA sensing in cancer: molecular mechanisms and therapeutic potential.","authors":"Addison A Young, Holly E Bohlin, Jackson R Pierce, Kyle A Cottrell","doi":"10.1042/BST20230727","DOIUrl":"https://doi.org/10.1042/BST20230727","url":null,"abstract":"<p><p>Immunotherapy has emerged as a therapeutic option for many cancers. For some tumors, immune checkpoint inhibitors show great efficacy in promoting anti-tumor immunity. However, not all tumors respond to immunotherapies. These tumors often exhibit reduced inflammation and are resistant to checkpoint inhibitors. Therapies that turn these 'cold' tumors 'hot' could improve the efficacy and applicability of checkpoint inhibitors, and in some cases may be sufficient on their own to promote anti-tumor immunity. One strategy to accomplish this goal is to activate innate immunity pathways within the tumor. Here we describe how this can be accomplished by activating double-stranded RNA (dsRNA) sensors. These sensors evolved to detect and respond to dsRNAs arising from viral infection but can also be activated by endogenous dsRNAs. A set of proteins, referred to as suppressors of dsRNA sensing, are responsible for preventing sensing 'self' dsRNA and activating innate immunity pathways. The mechanism of action of these suppressors falls into three categories: (1) Suppressors that affect mature RNAs through editing, degradation, restructuring, or binding. (2) Suppressors that affect RNA processing. (3) Suppressors that affect RNA expression. In this review we highlight suppressors that function through each mechanism, provide examples of the effects of disrupting those suppressors in cancer cell lines and tumors, and discuss the therapeutic potential of targeting these proteins and pathways.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intercellular communication within the tumor microenvironment (TME) is essential for establishing, mediating, and synchronizing cancer cell invasion and metastasis. Cancer cells, individually and collectively, react at the cellular and molecular levels to insults from standard-of-care treatments used to treat patients with cancer. One form of cell communication that serves as a prime example of cellular phenotypic stress response is a type of cellular protrusion called tunneling nanotubes (TNTs). TNTs are ultrafine, actin-enriched contact-dependent forms of membrane protrusions that facilitate long distance cell communication through transfer of various cargo, including genetic materials, mitochondria, proteins, ions, and various other molecules. In the past 5-10 years, there has been a growing body of evidence that implicates TNTs as a novel mechanism of cell-cell communication in cancer that facilitates and propagates factors that drive or enhance chemotherapeutic resistance in a variety of cancer cell types. Notably, recent literature has highlighted the potential of TNTs to serve as cellular conduits and mediators of drug and nanoparticle delivery. Given that TNTs have also been shown to form in vivo in a variety of tumor types, disrupting TNT communication within the TME provides a novel strategy for enhancing the cytotoxic effect of existing chemotherapies while suppressing this form of cellular stress response. In this review, we examine current understanding of interplay between cancer cells occurring via TNTs, and even further, the implications of TNT-mediated tumor-stromal cross-talk and the potential to enhance chemoresistance. We then examine tumor microtubes, an analogous cell protrusion heavily implicated in mediating treatment resistance in glioblastoma multiforme, and end with a brief discussion of the effects of radiation and other emerging treatment modalities on TNT formation.
{"title":"Do tunneling nanotubes drive chemoresistance in solid tumors and other malignancies?","authors":"Akshat Sarkari, Emil Lou","doi":"10.1042/BST20231364","DOIUrl":"10.1042/BST20231364","url":null,"abstract":"<p><p>Intercellular communication within the tumor microenvironment (TME) is essential for establishing, mediating, and synchronizing cancer cell invasion and metastasis. Cancer cells, individually and collectively, react at the cellular and molecular levels to insults from standard-of-care treatments used to treat patients with cancer. One form of cell communication that serves as a prime example of cellular phenotypic stress response is a type of cellular protrusion called tunneling nanotubes (TNTs). TNTs are ultrafine, actin-enriched contact-dependent forms of membrane protrusions that facilitate long distance cell communication through transfer of various cargo, including genetic materials, mitochondria, proteins, ions, and various other molecules. In the past 5-10 years, there has been a growing body of evidence that implicates TNTs as a novel mechanism of cell-cell communication in cancer that facilitates and propagates factors that drive or enhance chemotherapeutic resistance in a variety of cancer cell types. Notably, recent literature has highlighted the potential of TNTs to serve as cellular conduits and mediators of drug and nanoparticle delivery. Given that TNTs have also been shown to form in vivo in a variety of tumor types, disrupting TNT communication within the TME provides a novel strategy for enhancing the cytotoxic effect of existing chemotherapies while suppressing this form of cellular stress response. In this review, we examine current understanding of interplay between cancer cells occurring via TNTs, and even further, the implications of TNT-mediated tumor-stromal cross-talk and the potential to enhance chemoresistance. We then examine tumor microtubes, an analogous cell protrusion heavily implicated in mediating treatment resistance in glioblastoma multiforme, and end with a brief discussion of the effects of radiation and other emerging treatment modalities on TNT formation.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tolulope P Saliu, Jensen Goh, Gyumin Kang, Benjamin I Burke, Ahmed Ismaeel, John J McCarthy
Skeletal muscle stem cells (MuSCs) display distinct behavior crucial for tissue maintenance and repair. Upon activation, MuSCs exhibit distinct modes of division: symmetric division, facilitating either self-renewal or differentiation, and asymmetric division, which dictates divergent cellular fates. This review explores the nuanced dynamics of MuSC division and the molecular mechanisms governing this behavior. Furthermore, it introduces a novel phenomenon observed in a subset of MuSCs under hypertrophic stimuli termed division-independent differentiation. Insights into the underlying mechanisms driving this process are discussed, alongside its broader implications for muscle physiology.
{"title":"Satellite cell dynamics during skeletal muscle hypertrophy.","authors":"Tolulope P Saliu, Jensen Goh, Gyumin Kang, Benjamin I Burke, Ahmed Ismaeel, John J McCarthy","doi":"10.1042/BST20240201","DOIUrl":"10.1042/BST20240201","url":null,"abstract":"<p><p>Skeletal muscle stem cells (MuSCs) display distinct behavior crucial for tissue maintenance and repair. Upon activation, MuSCs exhibit distinct modes of division: symmetric division, facilitating either self-renewal or differentiation, and asymmetric division, which dictates divergent cellular fates. This review explores the nuanced dynamics of MuSC division and the molecular mechanisms governing this behavior. Furthermore, it introduces a novel phenomenon observed in a subset of MuSCs under hypertrophic stimuli termed division-independent differentiation. Insights into the underlying mechanisms driving this process are discussed, alongside its broader implications for muscle physiology.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cytokinin (CK) is a key plant hormone, but one whose effects are often misunderstood, partly due to reliance on older data from before the molecular genetic age of plant science. In this mini-review, we examine the role of CK in controlling the reproductive shoot architecture of flowering plants. We begin with a long overdue re-examination of the role of CK in shoot branching, and discuss the relatively paucity of genetic evidence that CK does play a major role in this process. We then examine the role of CK in determining the number of inflorescences, flowers, fruit and seed that plants initiate during reproductive development, and how these are arranged in space and time. The genetic evidence for a major role of CK in controlling these processes is much clearer, and CK has profound effects in boosting the size and number of most reproductive structures. Conversely, the attenuation of CK levels during the reproductive phase likely contributes to reduced organ size seen later in flowering, and the ultimate arrest of inflorescence meristems during end-of-flowering. We finish by discussing how this information can potentially be used to improve crop yields.
细胞分裂素(CK)是一种重要的植物激素,但它的作用常常被误解,部分原因是依赖于植物科学分子遗传时代之前的旧数据。在这篇微型综述中,我们将探讨细胞分裂素在控制开花植物生殖枝结构中的作用。首先,我们重新审视了 CK 在嫩枝分枝过程中的作用,并讨论了相对较少的遗传证据表明 CK 在这一过程中确实发挥了重要作用。然后,我们研究了 CK 在决定植物生殖发育过程中的花序、花朵、果实和种子数量方面的作用,以及这些花序、花朵、果实和种子在空间和时间上的排列方式。遗传学证据表明,CK 在控制这些过程中发挥着重要作用。相反,生殖期 CK 水平的降低可能会导致开花后期器官尺寸的缩小,以及花序分生组织在花期结束时的最终停止。最后,我们将讨论如何利用这些信息来提高作物产量。
{"title":"Cytokinin and reproductive shoot architecture: bigger and better?","authors":"Catriona H Walker, Tom Bennett","doi":"10.1042/BST20231565","DOIUrl":"10.1042/BST20231565","url":null,"abstract":"<p><p>Cytokinin (CK) is a key plant hormone, but one whose effects are often misunderstood, partly due to reliance on older data from before the molecular genetic age of plant science. In this mini-review, we examine the role of CK in controlling the reproductive shoot architecture of flowering plants. We begin with a long overdue re-examination of the role of CK in shoot branching, and discuss the relatively paucity of genetic evidence that CK does play a major role in this process. We then examine the role of CK in determining the number of inflorescences, flowers, fruit and seed that plants initiate during reproductive development, and how these are arranged in space and time. The genetic evidence for a major role of CK in controlling these processes is much clearer, and CK has profound effects in boosting the size and number of most reproductive structures. Conversely, the attenuation of CK levels during the reproductive phase likely contributes to reduced organ size seen later in flowering, and the ultimate arrest of inflorescence meristems during end-of-flowering. We finish by discussing how this information can potentially be used to improve crop yields.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ruaridh Lang, Rachel E Hodgson, Tatyana A Shelkovnikova
TDP-43 is an abundant and ubiquitously expressed nuclear protein that becomes dysfunctional in a spectrum of neurodegenerative diseases. TDP-43's ability to phase separate and form/enter biomolecular condensates of varying size and composition is critical for its functionality. Despite the high density of phase-separated assemblies in the nucleus and the nuclear abundance of TDP-43, our understanding of the condensate-TDP-43 relationship in this cellular compartment is only emerging. Recent studies have also suggested that misregulation of nuclear TDP-43 condensation is an early event in the neurodegenerative disease amyotrophic lateral sclerosis. This review aims to draw attention to the nuclear facet of functional and aberrant TDP-43 condensation. We will summarise the current knowledge on how TDP-43 containing nuclear condensates form and function and how their homeostasis is affected in disease.
{"title":"TDP-43 in nuclear condensates: where, how, and why.","authors":"Ruaridh Lang, Rachel E Hodgson, Tatyana A Shelkovnikova","doi":"10.1042/BST20231447","DOIUrl":"10.1042/BST20231447","url":null,"abstract":"<p><p>TDP-43 is an abundant and ubiquitously expressed nuclear protein that becomes dysfunctional in a spectrum of neurodegenerative diseases. TDP-43's ability to phase separate and form/enter biomolecular condensates of varying size and composition is critical for its functionality. Despite the high density of phase-separated assemblies in the nucleus and the nuclear abundance of TDP-43, our understanding of the condensate-TDP-43 relationship in this cellular compartment is only emerging. Recent studies have also suggested that misregulation of nuclear TDP-43 condensation is an early event in the neurodegenerative disease amyotrophic lateral sclerosis. This review aims to draw attention to the nuclear facet of functional and aberrant TDP-43 condensation. We will summarise the current knowledge on how TDP-43 containing nuclear condensates form and function and how their homeostasis is affected in disease.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jennifer Keller, James R O' Siorain, Thomas M Kündig, Mark Mellett
Interleukin-36 (IL-36) cytokines are structurally similar to other Interleukin-1 superfamily members and are essential to convey inflammatory responses at epithelial barriers including the skin, lung, and gut. Due to their potent effects on immune cells, IL-36 cytokine activation is regulated on multiple levels, from expression and activation to receptor binding. Different IL-36 isoforms convey specific responses as a consequence of particular danger- or pathogen-associated molecular patterns. IL-36 expression and activation are regulated by exogenous pathogens, including fungi, viruses and bacteria but also by endogenous factors such as antimicrobial peptides or cytokines. Processing of IL-36 into potent bioactive forms is necessary for host protection but can elevate tissue damage. Indeed, exacerbated IL-36 signalling and hyperactivation are linked to the pathogenesis of diseases such as plaque and pustular psoriasis, emphasising the importance of understanding the molecular aspects regulating IL-36 activation. Here, we summarise facets of the electrochemical properties, regulation of extracellular cleavage by various proteases and receptor signalling of the pro-inflammatory and anti-inflammatory IL-36 family members. Additionally, this intriguing cytokine subfamily displays many characteristics that are unique from prototypical members of the IL-1 family and these key distinctions are outlined here.
{"title":"Molecular aspects of Interleukin-36 cytokine activation and regulation.","authors":"Jennifer Keller, James R O' Siorain, Thomas M Kündig, Mark Mellett","doi":"10.1042/BST20230548","DOIUrl":"10.1042/BST20230548","url":null,"abstract":"<p><p>Interleukin-36 (IL-36) cytokines are structurally similar to other Interleukin-1 superfamily members and are essential to convey inflammatory responses at epithelial barriers including the skin, lung, and gut. Due to their potent effects on immune cells, IL-36 cytokine activation is regulated on multiple levels, from expression and activation to receptor binding. Different IL-36 isoforms convey specific responses as a consequence of particular danger- or pathogen-associated molecular patterns. IL-36 expression and activation are regulated by exogenous pathogens, including fungi, viruses and bacteria but also by endogenous factors such as antimicrobial peptides or cytokines. Processing of IL-36 into potent bioactive forms is necessary for host protection but can elevate tissue damage. Indeed, exacerbated IL-36 signalling and hyperactivation are linked to the pathogenesis of diseases such as plaque and pustular psoriasis, emphasising the importance of understanding the molecular aspects regulating IL-36 activation. Here, we summarise facets of the electrochemical properties, regulation of extracellular cleavage by various proteases and receptor signalling of the pro-inflammatory and anti-inflammatory IL-36 family members. Additionally, this intriguing cytokine subfamily displays many characteristics that are unique from prototypical members of the IL-1 family and these key distinctions are outlined here.</p>","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141465973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}