Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
ReviewHMGNs, DNA repair and cancer
Introduction
High mobility group N (HMGN) family contains five chromatin architectural proteins, which are present in higher vertebrates. Of these proteins, HMGN1, 2 and 4 are expressed ubiquitously [1], [2], while HMGN3 and 5 are expressed in specific tissues [3], [4]. The HMGNs bind specifically to nucleosome core particles, which consist of 147 bp of DNA, wrapped around an octamer of core histones. The binding of HMGNs to nucleosomes has no sequence specificity and is mediated by their nucleosomal binding domain (NBD), which is the hallmark of this family of proteins. In living cells, HMGNs bind to nucleosomes temporally in a stop-and-go fashion and move continuously between binding sites. However, at any given moment most of the HMGNs are bound to chromatin, since their residence time on nucleosomes is longer than their transit time between nucleosomes. This highly dynamic binding to nucleosomes enables the HMGNs to regulate the chromatin structure both locally and globally [5], [6], [7], [8]. HMGNs regulation of the chromatin structure is achieved by their ability to affect the levels of various histone post-translational modifications [9], [10], [11], to compete with histone H1 for chromatin binding sites [12], [13] and to modulate the activity of chromatin remodeling factors [14]. Through these modes of action the HMGNs can induce de-compaction of the chromatin fiber.
The DNA packaged inside the chromatin fiber is constantly damaged by multiple agents. The insulting agents originate from internal metabolic processes and from external sources such as ultraviolet light (UV) and ionizing irradiation (IR). DNA lesions impose barriers for processes occurring on the DNA fiber, such as transcription and replication. DNA lesions also lead to genetic mutations and chromosomal aberrations, which are among the main causes of cancer development [15], [16], [17]. Throughout evolution several systems have evolved to identify the different types of lesions in the DNA, to adjust the cellular physiology to the insult and to repair the damage [17], [18]. In humans, approximately 150 genes are dedicated to responding and repairing damage in the DNA [19]. In recent years, additional proteins, which were previously seen only as organizers of chromatin in relation to transcription and replication, were shown to have important roles in the cellular ability to respond to various types of DNA lesions. Among those proteins is HMGN1. This review will describe the roles recently found for HMGN1 in DNA damage response as well as in cancer progression and the potential found for HMGN2 as a therapeutic tool for cancer remission.
Section snippets
Role of HMGN1 in the cellular response to UV light
UV light induces several types of DNA lesions of which the cyclobutane pyrimidine dimers (CPD) and (6-4) pyrimidine-pyrimidone photoproducts [(6-4)PPs] are the most abundant [17], [18]. These lesions are repaired by the nucleotide excision repair (NER) pathway, which consists of two sub-pathways with different substrate specificity; global genome NER (GG-NER) and transcription-coupled repair (TCR). Both sub-pathways consist of ordered multi-step processes, which differ in the early steps, when
Role of HMGN1 in the cellular response to IR
Exposure of living organisms to IR leads to multiple types of DNA lesions including the double-stranded breaks (DSB), which are a dangerous insult for the stability of the genome. Formation of DSB in the genome leads to activation of a tightly regulated cascade of events termed DNA damage response (DDR), which controls the cellular response to the damage. In the DDR, the ternary protein complex MRN is the first recruit to the damage site. It facilitates the recruitment and activation of the
Role of HMGN1 in cancer progression
Cancer progression is thought to be dependent on the accumulation of mutations that change the transcriptional profile of the cell to support its escape from the tight regulation of cell cycle progression [51]. Improper responses to different types of DNA lesions that were detected in Hmgn1−/− cells and mice may lead to accumulation of mutations in the genome, which then accelerates the progression of the disease. In addition to the global effects of HMGN1 in the cellular response to DNA
Perspective
HMGNs are chromatin architectural proteins which until lately were considered to be transcription co-regulators. However, in recent years their role in DNA repair and cancer progression has been established primarily by using HMGN1 knock-out mice [24], [44], [45]. These studies suggest that the archetype of the HMGNs family, HMGN1, has characteristics of a tumor suppressor gene.
HMGNs act inside the cell in a network of chromatin architectural proteins that compete with histone H1 for nucleosome
Acknowledgments
This study was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH. I would like to thank M. Bustin (NCI), the NIH Fellows Editorial Board, R. Artzi-Gerlitz and V. Walker (NIH library) for constructive comments on the manuscript.
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HMG20A from Nile tilapia (Oreochromis niloticus) involved in the immune response to bacterial infection
2021, Fish and Shellfish ImmunologyCitation Excerpt :The HMGs protein family members are widely distributed, and they could bind to DNA and nucleosomes to induce changes in the chromatin structure; regulate DNA replication, transcription, and repair [2]; and serve as cytokines to participate in the inflammatory response caused by tissue damage [3–5]. Based on the differences of protein domains, HMGs were divided into three subgroups: HMGA (HMGA1a, HMGA1b, and HMGA1c) [6], HMGB (HMGB1, HMGB2, HMGB3, HMGB4, HMG20A, and HMG20B) [7–9], and HMGN [10], which had different functions [11,12]. HMG20A as a transcription factor has a typical HMG box domain (High mobility group) and has many important biological functions, such as inhibiting the differentiation of red blood cells and nerve cells, participating in the process of cytokinesis, and promoting the interstitial transformation of epidermal cells [13,14].
Pioneer Factors and Architectural Proteins Mediating Embryonic Expression Signatures in Cancer
2019, Trends in Molecular MedicineHigh mobility group (HMG) proteins: Modulators of chromatin structure and DNA repair in mammalian cells
2015, DNA RepairCitation Excerpt :Following DSB repair, specific chromatin remodeling complexes, such as INO80, are recruited to the damage site to assist in the reversal of these damage-induced chromatin changes [70]. Given the extent of chromatin reorganization that occurs following IR exposure, it should come as no surprise that the HMGN1 protein has been demonstrated to participate in various aspects of this process (recently reviewed in [27]). The first indication that this might be the case came from the observation that both knock-out Hmgn1−/− mice, and the MEF cells derived from them, exhibit hypersensitivity to IR exposure [42].
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