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Conclusion
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
Acknowledgements
Introduction Nucleosome, the basic chromatin unit, is composed of DNA and core histones (H2A, H2B, H3 and H4) and organized into high-order structures by diverse proteins including histone H1 and high mobility group (HMG) proteins. After histone proteins, HMG proteins are the second most abundant chromosomal proteins that are thought to play important roles in remodeling the assembly of chromatin and in regulating gene transcription in higher eukaryotic bosutinib by distorting, bending or modifying the structure of DNA, which is bound with histones and transcriptional factors [1,2]. HMG proteins, exhibiting molar masses of less than 30 kDa and relatively high mobility in acidic (pH 2.4) polyacrylamide gel electrophoresis system, were identified more than 30 years ago by Goodwin [3]. All HMG proteins bind to chromatin in a dynamic and reversible fashion and provide flexibility to chromatin to tune finely gene transcription either positively or negatively. Although the HMG proteins have never attracted the same degree of attention as histone proteins, they have been recently recognized to have essential roles in a variety of cellular processes, including cancer development [4], DNA repair [5] and infectious/inflammatory disorder [6]. All HMG proteins, like histone proteins, are subjected to a number of post-translational modifications (PTMs), such as lysine acetylation, arginine/lysine methylation and serine/threonine phosphorylation, which modulate their interactions with DNA and other proteins [7]. There is a growing appreciation for the complex relationship between the PTMs of HMG proteins and their diverse biological activities. Although the biological effects induced by the PTMs of HMG proteins are still not fully understood, new insights into the mechanism of the modification “code” have emerged from the increasing appreciation of the functions of these proteins in a variety of cellular processes from studies of human diseases and the development of mass spectrometric techniques. General overviews of HMG proteins as well as different subfamilies of HMG proteins have been written by a couple of groups [2,7–11]. Various reviews focusing on different aspects of HMG proteins are also available: the roles of HMG proteins in various diseases were reviewed by Fusco [4], Mantell [6] and Hock [12]; the implications of HMG proteins in DNA damage and repair were reviewed recently by Reeves [5] and Travers [13]; the detailed method for the preparation of different HMG family proteins were also described [14–17]. In this review, we will first discuss briefly the HMG protein members, their structure, function and implications in human diseases. We will then discuss in detail the post-translational modifications of the three families of mammalian HMG proteins, and highlight how these PTMs affect the functions of the HMG proteins in an array of cellular processes.
HMG protein members, their structure, function and implications in human diseases
PTMs of HMG proteins The PTMs of a protein determine/modulate its stability, folding, conformation, distribution, localization, turnover, and interaction with DNA or other proteins. Similar as histones, the biological activities of the HMG proteins are highly regulated by their post-translational modifications, including acetylation, methylation, phosphorylation, and ADP-ribosylation [10]. These secondary biochemical modifications are dynamic and rapidly responsive to intra- and extracellular signaling events. Since different families of HMG proteins have distinct modification profiles, hence different biological implications, next we will discuss separately the PTMs of HMGA, HMGB and HMGN proteins.
Conclusions and perspectives It is now clear that HMG proteins are essential in chromatin dynamics and they influence various DNA processes in the context of chromatin, which include transcription, replication, recombination and repair. Changes in HMG expression levels alter the cellular phenotype and lead to developmental abnormalities and diseases [12]. A large body of experimental evidence, as discussed above, indicates that HMG proteins participate in a wide range of cellular activities influenced by their post-translational modifications. Therefore, characterization of these chemical modifications of HMG proteins will provide significant insights into the mechanism of action of these proteins, which may eventually lead to improved detection, therapy and prognosis of human diseases.