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Seminars in Cell & Developmental Biology Dec 2022Every time a cell copies its DNA the genetic material is exposed to the acquisition of mutations and genomic alterations that corrupt the information passed on to... (Review)
Review
Every time a cell copies its DNA the genetic material is exposed to the acquisition of mutations and genomic alterations that corrupt the information passed on to daughter cells. A tight temporal regulation of DNA replication is necessary to ensure the full copy of the DNA while preventing the appearance of genomic instability. Protein modification by ubiquitin and SUMO constitutes a very complex and versatile system that allows the coordinated control of protein stability, activity and interactome. In chromatin, their action is complemented by the AAA+ ATPase VCP/p97 that recognizes and removes ubiquitylated and SUMOylated factors from specific cellular compartments. The concerted action of the ubiquitin/SUMO system and VCP/p97 determines every step of DNA replication enforcing the ordered activation/inactivation, loading/unloading and stabilization/destabilization of replication factors. Here we analyze the mechanisms used by ubiquitin/SUMO and VCP/p97 to establish molecular timers throughout DNA replication and their relevance in maintaining genome stability. We propose that these PTMs are the main molecular watch of DNA replication from origin recognition to replisome disassembly.
Topics: Humans; Cell Cycle Proteins; DNA; DNA Repair; DNA Replication; Genomic Instability; Ubiquitin; Sumoylation; Ubiquitination; Small Ubiquitin-Related Modifier Proteins
PubMed: 35210137
DOI: 10.1016/j.semcdb.2022.02.013 -
Current Opinion in Genetics &... Dec 2021Homologous Recombination (HR) is a critical DNA repair mechanism for a range of genome lesions. HR is responsible for mending DNA double strand breaks (DSBs) using... (Review)
Review
Homologous Recombination (HR) is a critical DNA repair mechanism for a range of genome lesions. HR is responsible for mending DNA double strand breaks (DSBs) using intact template DNA. In addition, many HR proteins help cope with DNA lesions generated from DNA replication and telomere deficiency. The functions of HR proteins are often regulated by protein modifications that can quickly and reversibly adjust substrate proteins' attributes. Sumoylation is one of the prevalent modifications that affects all steps of the HR processes and exerts diverse regulation on substrates. This review aims to summarize the most recent advances in our understanding of SUMO-based HR regulation and highlight some key questions that remain to be elucidated.
Topics: DNA Breaks, Double-Stranded; DNA Repair; Homologous Recombination; Protein Processing, Post-Translational; Sumoylation
PubMed: 34333341
DOI: 10.1016/j.gde.2021.07.007 -
Seminars in Cell & Developmental Biology Jul 2020SUMOylation is an evolutionarily conserved post-translational modification (PTM) that regulates protein subcellular localization, stability, conformation, transcription... (Review)
Review
SUMOylation is an evolutionarily conserved post-translational modification (PTM) that regulates protein subcellular localization, stability, conformation, transcription and enzymatic activity. Recent studies indicate that SUMOylation plays a key role in insulin gene expression, glucose metabolism and insulin exocytosis under physiological conditions in the pancreatic beta cells. Furthermore, SUMOylation is implicated in beta cell survival and recovery following exposure to oxidative stress, ER stress and inflammatory mediators under pathological situations. SUMOylation is closely regulated by the cellular redox status, and it collaborates with other PTMs such as phosphorylation, ubiquitination, and NEDDylation, to maintain beta cellular homeostasis. We hereby provide an update on recent findings regarding the role of SUMOylation in the regulation of pancreatic beta cell viability and function, and discuss its potential implication in beta cell senescence and RNA processing (e.g., pre-mRNA splicing and mRNA methylation). Through which we intend to provide novel insights into this fundamental biological process regarding both maintenance of beta cell viability and functionality, and beta cell dysfunction in diabetes mellitus.
Topics: Diabetes Mellitus; Humans; Insulin-Secreting Cells; Sumoylation
PubMed: 32331991
DOI: 10.1016/j.semcdb.2020.03.008 -
Plant Biotechnology Journal May 2022SUMOylation is involved in various aspects of plant biology, including drought stress. However, the relationship between SUMOylation and drought stress tolerance is...
SUMOylation is involved in various aspects of plant biology, including drought stress. However, the relationship between SUMOylation and drought stress tolerance is complex; whether SUMOylation has a crosstalk with ubiquitination in response to drought stress remains largely unclear. In this study, we found that both increased and decreased SUMOylation led to increased survival of apple (Malus × domestica) under drought stress: both transgenic MdSUMO2A overexpressing (OE) plants and MdSUMO2 RNAi plants exhibited enhanced drought tolerance. We further confirmed that MdDREB2A is one of the MdSUMO2 targets. Both transgenic MdDREB2A OE and MdDREB2A OE plants (which lacked the key site of SUMOylation by MdSUMO2A) were more drought tolerant than wild-type plants. However, MdDREB2A OE plants had a much higher survival rate than MdDREB2A OE plants. We further showed SUMOylated MdDREB2A was conjugated with ubiquitin by MdRNF4 under drought stress, thereby triggering its protein degradation. In addition, MdRNF4 RNAi plants were more tolerant to drought stress. These results revealed the molecular mechanisms that underlie the relationship of SUMOylation with drought tolerance and provided evidence for the tight control of MdDREB2A accumulation under drought stress mediated by SUMOylation and ubiquitination.
Topics: Droughts; Gene Expression Regulation, Plant; Malus; Plant Proteins; Plants, Genetically Modified; Stress, Physiological; Sumoylation
PubMed: 34978131
DOI: 10.1111/pbi.13772 -
European Journal of Cell Biology Jun 2023Intracellular calcium (Ca) has been reported to regulate transcription factor activity and cancer development, but how it affects the function of Forkhead box protein M1...
Intracellular calcium (Ca) has been reported to regulate transcription factor activity and cancer development, but how it affects the function of Forkhead box protein M1 (FOXM1), a crucial transcription factor and key oncogene participating in tumorigenesis, remains unclear. Here, we investigated the regulatory role of Ca on FOXM1 and found that Ca depletion caused the distribution of FOXM1 to aggregate on the nuclear envelope, which was also observed in many cell lines. Further experiments revealed that sequestrated FOXM1 colocalized with lamin B in the inner nuclear membrane (INM) and was affected by the activity of nuclear export protein exportin 1 (XPO1). To investigate how intracellular Ca affects FOXM1, we found that among the posttranscriptional modifications, only SUMOylation of FOXM1 showed a pronounced increase under reduced Ca, and suppressed SUMOylation rescued FOXM1 sequestration. In addition, Ca-dependent SUMOylated FOXM1 appeared to enhance the G2/M transition of the cell cycle and decrease cell apoptosis. In conclusion, our findings provide a molecular basis for the relationship between Ca signaling and FOXM1 regulation, and we look to elucidate Ca-dependent FOXM1 SUMOylation-related biological functions in the future.
Topics: Nuclear Envelope; Forkhead Transcription Factors; Sumoylation; M Cells; Forkhead Box Protein M1; Cell Cycle; Cell Proliferation; Gene Expression Regulation, Neoplastic; Cell Line, Tumor
PubMed: 37302175
DOI: 10.1016/j.ejcb.2023.151332 -
Neuromolecular Medicine Dec 2013Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and is the most common cause of dementia in the elderly.... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and is the most common cause of dementia in the elderly. Histopathologically, AD features insoluble aggregates of two proteins in the brain, amyloid-β (Aβ) and the microtubule-associated protein tau, both of which have been linked to the small ubiquitin-like modifier (SUMO). A large body of research has elucidated many of the molecular and cellular pathways that underlie AD, including those involving the abnormal Aβ and tau aggregates. However, a full understanding of the etiology and pathogenesis of the disease has remained elusive. Consequently, there are currently no effective therapeutic options that can modify the disease progression and slow or stop the decline of cognitive functioning. As part of the effort to address this lacking, there needs a better understanding of the signaling pathways that become impaired under AD pathology, including the regulatory mechanisms that normally control those networks. One such mechanism involves SUMOylation, which is a post-translational modification (PTM) that is involved in regulating many aspects of cell biology and has also been found to have several critical neuron-specific roles. Early studies have indicated that the SUMO system is likely altered with AD-type pathology, which may impact Aβ levels and tau aggregation. Although still a relatively unexplored topic, SUMOylation will likely emerge as a significant factor in AD pathogenesis in ways which may be somewhat analogous to other regulatory PTMs such as phosphorylation. Thus, in addition to the upstream effects on tau and Aβ processing, there may also be downstream effects mediated by Aβ aggregates or other AD-related factors on SUMO-regulated signaling pathways. Multiple proteins that have functions relevant to AD pathology have been identified as SUMO substrates, including those involved in synaptic physiology, mitochondrial dynamics, and inflammatory signaling. Ongoing studies will determine how these SUMO-regulated functions in neurons and glial cells may be impacted by Aβ and AD pathology. Here, we present a review of the current literature on the involvement of SUMO in AD, as well as an overview of the SUMOylated proteins and pathways that are potentially dysregulated with AD pathogenesis.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Brain; Humans; Mice; Nerve Tissue Proteins; Neurofibrillary Tangles; Plaque, Amyloid; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Synapses; Ubiquitin-Protein Ligase Complexes; tau Proteins
PubMed: 23979993
DOI: 10.1007/s12017-013-8257-7 -
Cellular & Molecular Biology Letters Jan 2024The eukaryotic translation initiation protein eIF5A is a highly conserved and essential factor that plays a critical role in different physiological and pathological...
BACKGROUND
The eukaryotic translation initiation protein eIF5A is a highly conserved and essential factor that plays a critical role in different physiological and pathological processes including stress response and cancer. Different proteomic studies suggest that eIF5A may be a small ubiquitin-like modifier (SUMO) substrate, but whether eIF5A is indeed SUMOylated and how relevant is this modification for eIF5A activities are still unknown.
METHODS
SUMOylation was evaluated using in vitro SUMOylation assays, Histidine-tagged proteins purification from His6-SUMO2 transfected cells, and isolation of endogenously SUMOylated proteins using SUMO-binding entities (SUBES). Mutants were engineered by site-directed mutagenesis. Protein stability was measured by a cycloheximide chase assay. Protein localization was determined using immunofluorescence and cellular fractionation assays. The ability of eIF5A1 constructs to complement the growth of Saccharomyces cerevisiae strains harboring thermosensitive mutants of a yeast EIF5A homolog gene (HYP2) was analyzed. The polysome profile and the formation of stress granules in cells expressing Pab1-GFP (a stress granule marker) by immunofluorescence were determined in yeast cells subjected to heat shock. Cell growth and migration of pancreatic ductal adenocarcinoma PANC-1 cells overexpressing different eIF5A1 constructs were evaluated using crystal violet staining and transwell inserts, respectively. Statistical analysis was performed with GraphPad Software, using unpaired Student's t-test, or one-way or two-way analysis of variance (ANOVA).
RESULTS
We found that eIF5A is modified by SUMO2 in vitro, in transfected cells and under endogenous conditions, revealing its physiological relevance. We identified several SUMO sites in eIF5A and found that SUMOylation modulates both the stability and the localization of eIF5A in mammalian cells. Interestingly, the SUMOylation of eIF5A responds to specific stresses, indicating that it is a regulated process. SUMOylation of eIF5A is conserved in yeast, the eIF5A SUMOylation mutants are unable to completely suppress the defects of HYP2 mutants, and SUMOylation of eIF5A is important for both stress granules formation and disassembly of polysomes induced by heat-shock. Moreover, mutation of the SUMOylation sites in eIF5A abolishes its promigratory and proproliferative activities in PANC-1 cells.
CONCLUSIONS
SUMO2 conjugation to eIF5A is a stress-induced response implicated in the adaptation of yeast cells to heat-shock stress and required to promote the growth and migration of pancreatic ductal adenocarcinoma cells.
Topics: Animals; Humans; Adenocarcinoma; Mammals; Proteomics; Saccharomyces cerevisiae; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Ubiquitin
PubMed: 38229033
DOI: 10.1186/s11658-024-00533-5 -
Electrophoresis Nov 2019Protein SUMOylation modification conjugated with small ubiquitin-like modifiers (SUMOs) is one kind of PTMs, which exerts comprehensive roles in cellular functions,... (Review)
Review
Protein SUMOylation modification conjugated with small ubiquitin-like modifiers (SUMOs) is one kind of PTMs, which exerts comprehensive roles in cellular functions, including gene expression regulation, DNA repair, intracellular transport, stress responses, and tumorigenesis. With the development of the peptide enrichment approaches and MS technology, more than 6000 SUMOylated proteins and about 40 000 SUMO acceptor sites have been identified. In this review, we summarize several popular approaches that have been developed for the identification of SUMOylated proteins in human cells, and further compare their technical advantages and disadvantages. And we also introduce identification approaches of target proteins which are co-modified by both SUMOylation and ubiquitylation. We highlight the emerging trends in the SUMOylation field as well. Especially, the advent of the clustered regularly interspaced short palindromic repeats/ Cas9 technique will facilitate the development of MS for SUMOylation identification.
Topics: CRISPR-Cas Systems; Cells, Cultured; Gene Editing; Humans; Mass Spectrometry; Models, Molecular; Peptides; Recombinant Fusion Proteins; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Ubiquitination
PubMed: 31216068
DOI: 10.1002/elps.201900100 -
Journal of Neurochemistry Jun 2016Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by cardinal motor signs such as rigidity, bradykinesia or rest tremor that... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by cardinal motor signs such as rigidity, bradykinesia or rest tremor that arise from a significant death of dopaminergic neurons. Non-dopaminergic degeneration also occurs and it seems to induce the deficits in olfactory, emotional, and memory functions that precede the classical motor symptoms in PD. Despite the majority of PD cases being sporadic, several genes have previously been associated with the hereditary forms of the disease. The proteins encoded by some of these genes, including α-synuclein, DJ-1, and parkin, are modified by small ubiquitin-like modifier (SUMO), a post-translational modification that regulates a variety of cellular processes. Among the several pathogenic mechanisms proposed for PD is mitochondrial dysfunction. Recent studies suggest that SUMOylation can interfere with mitochondrial dynamics, which is essential for neuronal function, and may play a pivotal role in PD pathogenesis. Here, we present an overview of recent studies on mitochondrial disturbance in PD and the potential SUMO-modified proteins and pathways involved in this process. SUMOylation, a post-translational modification, interferes with mitochondrial dynamics, and may play a pivotal role in Parkinson's disease (PD). SUMOylation maintains α-synuclein (α-syn) in a soluble form and activates DJ-1, decreasing mitochondrial oxidative stress. SUMOylation may reduce the amount of parkin available for mitochondrial recruitment and decreases mitochondrial biogenesis through suppression of peroxisomal proliferator-activated receptor-γ co-activator 1 α (PGC-1α). Mitochondrial fission can be regulated by dynamin-related protein 1 SUMO-1- or SUMO-2/3-ylation. A fine balance for the SUMOylation/deSUMOylation of these proteins is required to ensure adequate mitochondrial function in PD.
Topics: Animals; Dopaminergic Neurons; Humans; Mitochondria; Oxidative Stress; Parkinson Disease; Small Ubiquitin-Related Modifier Proteins; Sumoylation
PubMed: 26932327
DOI: 10.1111/jnc.13599 -
Biochemical Society Transactions Apr 2024The preservation of genome integrity requires specialised DNA damage repair (DDR) signalling pathways to respond to each type of DNA damage. A key feature of DDR is the... (Review)
Review
The preservation of genome integrity requires specialised DNA damage repair (DDR) signalling pathways to respond to each type of DNA damage. A key feature of DDR is the integration of numerous post-translational modification signals with DNA repair factors. These modifications influence DDR factor recruitment to damaged DNA, activity, protein-protein interactions, and ultimately eviction to enable access for subsequent repair factors or termination of DDR signalling. SUMO1-3 (small ubiquitin-like modifier 1-3) conjugation has gained much recent attention. The SUMO-modified proteome is enriched with DNA repair factors. Here we provide a snapshot of our current understanding of how SUMO signalling impacts the major DNA repair pathways in mammalian cells. We highlight repeating themes of SUMO signalling used throughout DNA repair pathways including the assembly of protein complexes, competition with ubiquitin to promote DDR factor stability and ubiquitin-dependent degradation or extraction of SUMOylated DDR factors. As SUMO 'addiction' in cancer cells is protective to genomic integrity, targeting components of the SUMO machinery to potentiate DNA damaging therapy or exacerbate existing DNA repair defects is a promising area of study.
Topics: Humans; DNA Damage; DNA Repair; Small Ubiquitin-Related Modifier Proteins; Animals; Sumoylation; Signal Transduction; Protein Processing, Post-Translational; Ubiquitin
PubMed: 38629643
DOI: 10.1042/BST20230862