Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
ReviewHMG modifications and nuclear function
Introduction
The genetic material within the nucleus of eukaryotic cells exists in the form of chromatin, which functions as an integrated platform for the dynamic regulation of various nuclear processes, such as transcription, replication and repair. The basic building block of chromatin is nucleosome, which consists of DNA and core histones (H2A, H2B, H3 and H4). Nucleosomes are modified and organized into higher-order structures by histone H1 and other abundant chromosomal proteins, among which high mobility group (HMG) proteins represent the largest group of non-histone components [1], [2], [3]. HMG proteins play important roles in remodeling the assembly of chromatin and regulating gene transcription in higher eukaryotic cells by distorting, bending or modifying the structure of DNA, which forms complexes with histones and transcription factors [1], [3], [4].
Three distinct families of HMG proteins were defined and named after the structure of their DNA binding domains as well as their substrate binding specificity, including HMG-AT-hook families (HMGA), HMG-box families (HMGB) and HMG-nucleosome binding families (HMGN) [5]. Similar to histones, HMG proteins are subject to a wide range of post-translational modifications (PTMs) as shown in Fig. 1, including lysine acetylation/methylation/formylation/SUMOylation, arginine methylation and serine/threonine phosphorylation, etc. A large body of experimental evidence indicates that HMG proteins, which are highly regulated by their PTMs, are essential players in the execution and regulation of nuclear functions. Characterization of these chemical modifications of HMG proteins has and will continue to provide significant insights into the mechanisms of action of these proteins, which may eventually lead to improved diagnosis, therapy and prognosis of human diseases. In this review, we discuss common modifications of mammalian HMG proteins, with emphasis being placed on recent findings about the roles of these modifications in nuclear functions.
Section snippets
PTMs of HMGA proteins
The HMGA proteins, comprising of HMGA1a, HMGA1b and HMGA2, are characterized by the possession of three DNA-binding domains known as “AT-hooks” [6] and an acidic carboxyl-terminal tail. They are involved in a wide variety of nuclear processes by regulating, positively or negatively, transcriptional activities of numerous genes in vivo [7], [8]. Through interactions with DNA and other proteins, they influence normal biological processes such as cell growth, proliferation, differentiation and
PTMs of HMGB proteins
HMGB proteins, including HMGB1 (formerly known as HMG1), HMGB2 (previously HMG2) and HMGB3, contain two HMG-box domains and a highly acidic C-terminal tail. The HMG boxes bend DNA and bind preferentially to structurally distorted DNA [62].
In the nucleus, HMGB proteins regulate numerous activities such as transcription, replication and repair [3], [63]. The Hmgb1 knockout mice die shortly after birth, supporting the functional importance of the HMGB1 protein [64]. One mechanism for HMGB proteins
PTMs of HMGN proteins
Among all HMG proteins, HMGN is the only subgroup known to bind specifically to the 147-base pair nucleosome core particle [86], [87]. The major members, HMGN1 and HMGN2, are present in the nuclei of all mammalian and most vertebrate cells [1], [2]. There are three major functional domains in HMGN proteins: a nucleosome-binding domain (NBD), a bipartite nuclear localization signal (NLS) and a chromatin-unfolding domain (CHUD) [88], [89], [90]. The NBD domain is a highly conserved and positively
Conclusions
HMG proteins participate in a wide range of cellular activities influenced by their post-translational modifications. Characterization of these modifications of HMG proteins has and will continue to yield significant insights into the biological functions of these proteins. Recent years have witnessed continuing discovery in the diversity and complexity of HMG modifications that are functionally important in distinct cellular pathways. The enzymes involved with the deposition of some of these
Acknowledgments
The authors want to thank the National Institutes of Health for supporting this research (R01 CA116522) and Dr. Yan Zou for helpful discussion.
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