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BBA - Gene Regulatory Mechanisms (v.1799, #1-2)
Nuclear functions of the HMG proteins by Raymond Reeves (pp. 3-14).
Although the three families of mammalian HMG proteins (HMGA, HMGB and HMGN) participate in many of the same nuclear processes, each family plays its own unique role in modulating chromatin structure and regulating genomic function. This review focuses on the similarities and differences in the mechanisms by which the different HMG families impact chromatin structure and influence cellular phenotype. The biological implications of having three architectural transcription factor families with complementary, but partially overlapping, nuclear functions are discussed.
Binding and interplay of HMG proteins on chromatin: Lessons from live cell imaging by Fred Catez; Robert Hock (pp. 15-27).
Members of the superfamily of high mobility group (HMG) proteins are considered as architectural elements of chromatin. It is now clear that they belong to a network of dynamic chromatin proteins that constantly move around the chromatin fiber thereby dynamically modulating DNA-dependent processes. In this review we discuss how HMGs fused to fluorescent proteins and live cell imaging advanced our understanding in HMG dynamics and function. By presenting the regulation of the dynamic properties of each HMG family in comparison to one another we wish to highlight common themes among the three families, as well as stimulate new ideas from one HMG family in relation to the others and more generally in the dynamic world of chromatin.
Keywords: HMG-proteins; GFP; Live cell imaging
HMG modifications and nuclear function by Qingchun Zhang; Yinsheng Wang (pp. 28-36).
High mobility group (HMG) proteins assume important roles in regulating chromatin dynamics, transcriptional activities of genes and other cellular processes. Post-translational modifications of HMG proteins can alter their interactions with DNA and proteins, and consequently, affect their biological activities. Although the mechanisms through which these modifications are involved in regulating biological processes in different cellular contexts are not fully understood, new insights into these modification “codes” have emerged from the increasing appreciation of the functions of these proteins. In this review, we focus on the chemical modifications of mammalian HMG proteins and highlight their roles in nuclear functions.
Keywords: High mobility group protein; Post-translational modification; Mass spectrometry
HMGA molecular network: From transcriptional regulation to chromatin remodeling by Riccardo Sgarra; Salvina Zammitti; Alessandra Lo Sardo; Elisa Maurizio; Laura Arnoldo; Silvia Pegoraro; Vincenzo Giancotti; Guidalberto Manfioletti (pp. 37-47).
Nuclear functions rely on the activity of a plethora of factors which mostly work in highly coordinated molecular networks. The HMGA proteins are chromatin architectural factors which constitute critical hubs in these networks. HMGA are referred to as oncofetal proteins since they are highly expressed and play essential functions both during embryonic development and neoplastic transformation. A particular feature of HMGA is their intrinsically disordered status, which confers on them an unusual plasticity in contacting molecular partners. Indeed these proteins are able to bind to DNA at the level of AT-rich DNA stretches and to interact with several nuclear factors. In the post-genomic era, and with the advent of proteomic tools for the identification of protein–protein interactions, the number of HMGA molecular partners has increased rapidly. This has led to the extension of our knowledge of the functional involvement of HMGA from the transcriptional regulation field to RNA processing, DNA repair, and chromatin remodeling and dynamics. This review focuses mainly on the protein–protein interaction network of HMGA and its functional outcome. HMGA molecular partners have been functionally classified and all the information collected in a freely available database (http://www.bbcm.units.it/∼manfiol/INDEX.HTM).
Keywords: Intrinsically disordered proteins; Protein–protein interaction; Architectural transcription factors; Cancer
HMGA and Cancer by Monica Fedele; Alfredo Fusco (pp. 48-54).
Long-standing studies have clearly established that the architectural chromatinic proteins High Mobility Group A (HMGA) are among the most widely expressed cancer-associated proteins. Indeed, their overexpression represents a constant feature of human malignancies, and correlates with a poor prognosis. Moreover, HMGA dysregulation, as a result of specific chromosomal rearrangements, occurs in a broad variety of common benign mesenchymal tumors, making HMGA genes among the most commonly rearranged genes in human neoplasms. Nevertheless, recent data propose a critical role of HMGA overexpression also in the generation of pituitary adenomas.Here, we review the involvement of HMGA proteins in cancer, analyzing the mechanisms underlying their crucial role in tumorigenesis, and, finally, discuss the potentiality of a cancer treatment based on HMGA targeting.
Keywords: High Mobility Group protein; Chromatinic protein; Mesenchymal tumor; Pituitary adenomas; Carcinogenesis
In vivo modulation of HMGA2 expression by Hena R. Ashar; Roland A. Chouinard Jr.; Madhavi Dokur; Kiran Chada (pp. 55-61).
While the biochemical role of the HMGA proteins has largely been elucidated in tissue culture, the majority of the insight as to their physiological functions in the processes of proliferation and development has been established in animal models of overexpression (transgenic) and null mice (knockouts). An emphasis has been placed on the HMGA2 studies which have defined its critical role in mesenchymal proliferation and differentiation.
Keywords: HMGA2; Mesenchymal proliferation; Adipogenesis; Spermatogenesis
Regulation of chromatin structure and function By HMGN proteins by Yuri Postnikov; Michael Bustin (pp. 62-68).
High mobility group nucleosome-binding (HMGN) proteins are architectural non-histone chromosomal proteins that bind to nucleosomes and modulate the structure and function of chromatin. The interaction of HMGN proteins with nucleosomes is dynamic and the proteins compete with the linker histone H1 chromatin-binding sites. HMGNs reduce the H1-mediated compaction of the chromatin fiber and facilitate the targeting of regulatory factors to chromatin. They modulate the cellular epigenetic profile, affect gene expression and impact the biological processes such as development and the cellular response to environmental and hormonal signals. Here we review the role of HMGN in chromatin structure, the link between HMGN proteins and histone modifications, and discuss the consequence of this link on nuclear processes and cellular phenotype.
Keywords: High Mobility Group Protein; Chromatin; Nucleosomes; Histones; Epigenesis
Developmental function of HMGN proteins by Takashi Furusawa; Srujana Cherukuri (pp. 69-73).
High mobility group N (HMGN) proteins are the only nuclear proteins known to specifically recognize the generic structure of the 147-bp nucleosome core particle. Both in vitro and in vivo experiments demonstrate that HMGN proteins are involved in epigenetic regulation by modulating chromatin structure and levels of posttranslational modifications of nucleosomal histones. Expression of HMGN proteins is developmentally regulated, and the loss or overexpression of these proteins can lead to developmental abnormalities. This review will focus on the role and on the possible molecular mechanism whereby HMGN proteins affect cellular differentiation and development.
Keywords: HMGN protein; Chromatin; Embryogenesis; Differentiation
Transcriptional regulation by HMGN proteins by Nan Zhu; Ulla Hansen (pp. 74-79).
High mobility group nucleosomal proteins (HMGNs) are small non-histone proteins associated with chromatin. HMGNs have the unique ability to bind to nucleosomes with higher affinity than to naked DNA . They have been studied extensively for their ability to modulate transcription. Although initially viewed as general transcriptional activators on chromatin templates, it is now appreciated that they are instead highly specific modulators of gene expression. We review the mechanisms for targeting HMGNs to specific genes and for how they subsequently regulate transcription.
Keywords: HMGN; Chromatin; Transcription; Transcription factor; Chromatin remodeling; Protein modification
HMGNs, DNA repair and cancer by Gabi Gerlitz (pp. 80-85).
DNA lesions threaten the integrity of the genome and are a major factor in cancer formation and progression. Eukaryotic DNA is organized in nucleosome-based higher order structures, which form the chromatin fiber. In recent years, considerable knowledge has been gained on the importance of chromatin dynamics for the cellular response to DNA damage and for the ability to repair DNA lesions. High Mobility Group N1 (HMGN1) protein is an emerging factor that is important for chromatin alterations in response to DNA damage originated from both ultra violet light (UV) and ionizing irradiation (IR). HMGN1 is a member in the HMGN family of chromatin architectural proteins. HMGNs bind directly to nucleosomes and modulate the structure of the chromatin fiber in a highly dynamic manner. This review focuses mainly on the roles of HMGN1 in the cellular response pathways to different types of DNA lesions and in transcriptional regulation of cancer-related genes. In addition, emerging roles for HMGN5 in cancer progression and for HMGN2 as a potential tool in cancer therapy will be discussed.
Keywords: HMGN proteins; Nucleotide excision repair; Transcription coupled repair; Double-strand breaks; DNA damage response; Histone H1
HMGN5/NSBP1: A new member of the HMGN protein family that affects chromatin structure and function by Mark Rochman; Cedric Malicet; Michael Bustin (pp. 86-92).
The dynamic nature of the chromatin fiber provides the structural and functional flexibility required for the accurate transcriptional responses to various stimuli. In living cells, structural proteins such as the linker histone H1 and the high mobility group (HMG) proteins continuously modulate the local and global architecture of the chromatin fiber and affect the binding of regulatory factors to their nucleosomal targets. HMGN proteins specifically bind to the nucleosome core particle through a highly conserved “nucleosomal binding domain” (NBD) and reduce chromatin compaction. HMGN5 (NSBP1), a new member of the HMGN protein family, is ubiquitously expressed in mouse and human tissues. Similar to other HMGNs, HMGN5 is a nuclear protein which binds to nucleosomes via NBD, unfolds chromatin, and affects transcription. This protein remains mainly uncharacterized and its biological function is unknown. In this review, we describe the structure of the HMGN5 gene and the known properties of the HMGN5 protein. We present recent findings related to the expression pattern of the protein during development, the mechanism of HMGN5 action on chromatin, and discuss the possible role of HMGN5 in pathological and physiological processes.
Keywords: HMGN5; NSBP1; Chromatin; Linker histone H1; Transcription; Nucleosome
Signalling to chromatin through post-translational modifications of HMGN by Edgar A. Pogna; Alison L. Clayton; Louis C. Mahadevan (pp. 93-100).
The DNA of eukaryotic genomes is highly packaged by its organisation into chromatin, the fundamental repeating unit of which is the nucleosome core particle, consisting of 147 base pairs of DNA wrapped around an octamer of two copies each of the four core histone proteins H2A, H2B, H3 and H4 (K. Luger, A.W. Mader, R.K. Richmond, D.F. Sargent, T.J. Richmond, Crystal structure of the nucleosome core particle at 2.8 A resolution, Nature 389 (1997) 251-260 and references therein). Accessibility of DNA within chromatin is a central factor that affects DNA-dependent nuclear function such as transcription, replication, recombination and repair. To integrate complex signalling networks associated with these events, many protein and multi-protein complexes associate transiently with nucleosomes. One class of such are the High-Mobility Group (HMG) proteins which are architectural DNA and nucleosome-binding proteins that may be subdivided into three families; HMGA (HMGI/Y/C), HMGB (HMG1/2) and HMGN (HMG14/17). The structure of chromatin and nucleosomes can be altered, both locally and globally, by interaction with such architectural proteins thereby influencing accessibility of DNA. This chapter deals with the HMGN protein family, specifically their post-translational modification as part of regulatory networks. We focus particularly on HMGN1, the most extensively studied family member to date, and to a lesser extent on HMGN2. We critically evaluate evidence for the role of post-translational modification of these proteins in response to different signals, exploring the sites and potential significance of such modification.
Keywords: HMGN; Post-translational modification; Acetylation; Phosphorylation; Immediate-Early gene induction; Nucleocytoplasmic transport
HMGB proteins: Interactions with DNA and chromatin by Michal Štros (pp. 101-113).
HMGB proteins are members of the High Mobility Group (HMG) superfamily, possessing a unique DNA-binding domain, the HMG-box, which can bind non-B-type DNA structures (bent, kinked and unwound) with high affinity, and also distort DNA by bending/looping and unwinding. HMGBs (there are four HMGBs in mammals, HMGB1–4) are highly abundant and ubiquitously expressed non-histone proteins, acting as DNA chaperones influencing multiple processes in chromatin such as transcription, replication, recombination, DNA repair and genomic stability. Although HMGB1 is a nuclear protein, it can be secreted into the extracellular milieu as a signaling molecule when cells are under stress, in particular, when necrosis occurs. Mammalian HMGBs contain two HMG-boxes arranged in tandem, share more than 80% identity and differ in the length (HMGB1-3) or absence (HMGB4) of the acidic C-tails. The acidic tails consist of consecutive runs of only Glu/Asp residues of various length, and modulate the DNA-binding properties and functioning of HMGBs. HMGBs are subject to post-translational modifications which can fine-tune interactions of the proteins with DNA/chromatin and determine their relocation from the nucleus to the cytoplasm and secretion. Association of HMGBs with chromatin is highly dynamic, and the proteins affect the chromatin fiber as architectural factors by transient interactions with nucleosomes, displacement of histone H1, and facilitation of nucleosome remodeling and accessibility of the nucleosomal DNA to transcription factors or other sequence-specific proteins.
Keywords: HMGB; HMG-box; Architectural protein; DNA–protein interaction; Chromatin
HMGB proteins and transcriptional regulation by Tetsuya Ueda; Michiteru Yoshida (pp. 114-118).
In eukaryotic nuclei, transcription reactions on the chromatin are regulated by the binding of transcription regulators such as transcription factors and chromatin remodeling factors to chromatin. High-mobility-group-box (HMGB) protein family is a member of HMG super family proteins, the most abundant and ubiquitous non-histone chromatin binding proteins in eukaryotic cells. HMGB proteins bind to chromosomal DNA via their DNA binding motif, a HMG box, and induce structural changes of chromatin. Besides the chromatin binding property of HMGB proteins, HMGB proteins also interact with other proteins including transcription regulators and histones. In addition to those key transcriptional regulatory proteins, undoubtedly HMGB proteins bind dynamically to chromatin and interact with other proteins including transcription factors, thereby participating in transcription regulation in multiple processes. We will focus on the transcription regulation by HMGB proteins bound to chromatin, and possible roles of the unique structural and functional domain, the acidic C-tail region.
Keywords: High mobility group; HMGB; Chromatin; Transcription
HMGB1: Roles in base excision repair and related function by Yuan Liu; Rajendra Prasad; Samuel H. Wilson (pp. 119-130).
High mobility group box 1 (HMGB1) is a nonhistone architectural protein that is involved in many biological processes including chromatin remodeling, transcription, cell signaling of inflammation, DNA damage repair and others. Recent studies have identified the cross-link of HMGB1 with a DNA base excision repair intermediate indicating that this protein is involved in base excision repair (BER) pathway. Further characterization of the roles of HMGB1 in BER demonstrates that the protein acts as a cofactor to regulate BER sub-pathways by inhibiting single-nucleotide BER and stimulating long-patch BER through modulating the activities of base excision repair enzymes. Directing of base lesion repair to the long-patch sub-pathway can result in trinucleotide repeat instability suggesting an important role of HMGB1 in modulating genome stability.
Keywords: HMGB1; DNA binding; DNA bending; Base excision repair; AP endonuclease; FEN1; Trinucleotide repeat expansion
High-mobility group box 1 and cancer by Daolin Tang; Rui Kang; Herbert J. Zeh III; Michael T. Lotze (pp. 131-140).
High-mobility group box 1 protein (HMGB1), a chromatin associated nuclear protein and extracellular damage associated molecular pattern molecule (DAMP), is an evolutionarily ancient and critical regulator of cell death and survival. Overexpression of HMGB1 is associated with each of the hallmarks of cancer including unlimited replicative potential, ability to develop blood vessels (angiogenesis), evasion of programmed cell death (apoptosis), self-sufficiency in growth signals, insensitivity to inhibitors of growth, inflammation, tissue invasion and metastasis. Our studies and those of our colleagues suggest that HMGB1 is central to cancer (abnormal wound healing) and many of the findings in normal wound healing as well. Here, we focus on the role of HMGB1 in cancer, the mechanisms by which it contributes to carcinogenesis, and therapeutic strategies based on targeting HMGB1.
Keywords: HMGB1; Damage associated molecular pattern molecule [DAMP]; Autophagy; Cancer; Angiogenesis; Receptor for advanced glycation endproducts [RAGE]; TLR2; TLR4; CD24; TLR9; Hallmarks of cancer; Field effect; Inflammation
The role of HMGB1 in the pathogenesis of rheumatic disease by Ulf Andersson; Helena Erlandsson Harris (pp. 141-148).
HMGB1 is a ubiquitous nuclear protein that can be released by any damaged cell or by activated macrophages and certain other cell types. HMGB1 has been successfully therapeutically targeted in multiple preclinical models of infectious and sterile diseases including arthritis. Extracellular HMGB1 mediates inflammation via induction of cytokine and metalloproteinase production and recruitment and activation of dendritic cells needed for priming of naïve T helper type 1 lymphocytes. HMGB1 can bind endogenous molecules such as IL-1β and nucleosomes and exogenous agents like endotoxin and microbial DNA. These complexes synergistically increase the capacity for activation of adaptive and innate immunity. HMGB1–nucleosome complexes induce autoantibody formation against double-stranded DNA and nucleosomes, which does not occur if HMGB1 is absent. These antibodies are central in the pathogenesis of systemic lupus erythematosus and patients with active disease have both increased HMGB1 and HMGB1-nucleosome levels in circulation. Furthermore, HMGB1 is strongly bipolar charged, enabling cell membrane passage and intracellular transport of complexed molecules including DNA. Rheumatoid arthritis patients have excessive extracellular HMGB1 levels in joints and serum. The HMGB1 release is caused by cytokines, activated complement and hypoxia. The most prominent HMGB1 protein and mRNA expression arthritis is present in pannus regions, where synovial tissue invades articular cartilage and bone. HMGB1 promotes the activity of proteolytic enzymes, and osteoclasts need HMGB1 for functional maturation. Neutralizing HMGB1 therapy in preclinical models of arthritis confers striking protection against structural damage. This review summarizes selected aspects of HMGB1 biology relevant for induction and propagation of some autoimmune conditions.
Keywords: HMGB1; Inflammation; Rheumatic diseases; Necrosis; Apoptosis; Therapy
Targeting HMGB1 in inflammation by Huan Yang; Kevin J. Tracey (pp. 149-156).
High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein present in the nuclei and cytoplasm of nearly all cell types, is a necessary and sufficient mediator of inflammation during sterile and infection-associated responses. Elevated levels of HMGB1 in serum and tissues occur during sterile tissue injury and during infection, and targeting HMGB1 with antibodies or specific antagonists is protective in established preclinical inflammatory disease models including lethal endotoxemia or sepsis, collagen-induced arthritis, and ischemia–reperfusion induced tissue injury. Future advances in this field will stem from understanding the biological basis for the success of targeting HMGB1 to therapeutic improvement in the treatment of inflammation, infection and ischemia–reperfusion induced injury.
Keywords: Cytokine; HMGB1; Inflammation; Immune response; Receptor
The alarmin functions of high-mobility group proteins by De Yang; Poonam Tewary; Gonzalo de la Rosa; Feng Wei; Joost J. Oppenheim (pp. 157-163).
High-mobility group (HMG) proteins are non-histone nuclear proteins that bind nucleosomes and regulate chromosome architecture and gene transcription. Over the past decade, numerous studies have established that some HMG proteins can be released extracellularly and demonstrate distinct extracellular biological activities. Here, we will give a brief overview of HMG proteins and highlight their participation in innate/inflammatory and adaptive immune responses. They have the activities of alarmins, which are endogenous mediators that are rapidly released in response to danger signals initiated by infection and/or tissue damage and are capable of activating innate and adaptive immunity by promoting the recruitment and activation of antigen-presenting cells (APCs).
Keywords: High-mobility group protein; Alarmin; Dendritic cells; Immune response
Physiological and pathophysiological outcomes of the interactions of HMGB1 with cell surface receptors by Heikki Rauvala; Ari Rouhiainen (pp. 164-170).
Extracellularly occurring HMGB1, either released during cell injury or actively secreted from cells, has profound effects on behaviour of a wide variety of cell types. Extracellular HMGB1 regulates migratory responses of many cell types, including neuron and growth cone migration, invasive migration of tumour cells, and migration of endothelial and immune cells. RAGE (Receptor for Advanced Glycation End Products) plays a key role as a cell surface receptor in most, if not all HMGB1-dependent migration mechanisms. HMGB1 binds to the distal immunoglobulin-like domain of RAGE, activating a signalling pathway that ends up in modulation of the cytoskeleton for regulation of cell motility. In addition to RAGE, proteoglycans and sulfated carbohydrate epitopes of glycolipids and glycoproteins may play a role as cell surface binding sites of HMGB1, affecting migratory behaviour of cells.In addition to physiological and pathophysiological cell migration control, HMGB1 has been widely studied as a molecule linking tissue injury to inflammatory mechanisms. HMGB1 by itself has little if any proinflammatory activity but it appears to activate innate immunity mechanisms as a complex with DNA, lipids and/or proinflammatory cytokines. The inflammation-inducing activity of HMGB1/DNA complexes may depend on both RAGE and Toll-like receptors of the immune cell surface. In addition to the receptors activating innate immunity, receptors downregulating inflammation upon HMGB1 release have been recently found, and include thrombomodulin and the CD-24/Siglec pathway.
Keywords: HMGB1; Amphoterin; RAGE; Proteoglycan; Toll-like receptors; Cell migration
The role of chromosomal HMGB proteins in plants by Dorthe S. Pedersen; Klaus D. Grasser (pp. 171-174).
Proteins belonging to the chromosomal HMGA and HMGB families have been identified in a broad range of plant species. In this article, we describe the family of HMGB proteins, which, in plants, are more diversified than in other eukaryotes. There are differences between various plant HMGB proteins regarding several properties including expression pattern, DNA– and chromatin–interactions, posttranslational modifications, subcellular localisation, and interaction with other proteins, suggesting that plants have a broad repertoire of these architectural chromosomal proteins. Recent results in the Arabidopsis model system indicate that the HMGB proteins have (partially) specialised functions and are required for proper development. In addition, they are involved in plant tolerance to different stress conditions.
Keywords: High mobility group (HMG) protein; HMGB; Plant chromatin; Development; Stress tolerance
Nhp6: A small but powerful effector of chromatin structure in Saccharomyces cerevisiae by David J. Stillman (pp. 175-180).
The small Nhp6 protein from budding yeast is an abundant protein that binds DNA non-specifically and bends DNA sharply. It contains only a single HMGB domain that binds DNA in the minor groove and a basic N-terminal extension that wraps around DNA to contact the major groove. This review describes the genetic and biochemical experiments that indicate Nhp6 functions in promoting RNA pol III transcription, in formation of preinitiation complexes at promoters transcribed by RNA pol II, and in facilitating the activity of chromatin modifying complexes. The FACT complex may provide a paradigm for how Nhp6 functions with chromatin factors, as Nhp6 allows Spt16-Pob3 to bind to and reorganize nucleosomes in vitro.
Keywords: HMGB; Chromatin; Nucleosome; Pol II; Pol III; TBP; TFIIA; TFIIB; FACT; Spt16; Pob3; Swi/Snf; Rsc