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  • It is now thought that tight binding

    2023-01-24

    It is now thought that tight binding of HMGB to condensed chromatin may not be restricted to apoptotic cells. That HMGB proteins might actually be involved in the organization and/or maintenance of heterochromatic regions is suggested by the results of experiments analyzing the stable binding of the HMGB2 protein, in complex with nucleolin and YY1 proteins, to the heterochromatic DZ4Z tandem repeat sequences in the subtelomeric region of human 4q35 [59]. Thus, like the HMGA proteins, the HMGB proteins can impact the structure of chromatin at both the local nucleosomal level and on larger, much more extensive scales.
    HMGN proteins and chromatin structure The six principal members of the HMGN (formerly called HMG-14 and -17) protein family (HMGN1, HMGN2, HMGN3a, HMGN3b, HMGN4 and HMGN5) are found only in vertebrates [24]. Detailed studies of developing vertebrate embryos show that the levels of expression HMGN proteins are tightly linked to cellular differentiation [57,80]. For example, during mouse embryogenesis, the level of expression of the two major protein variants, HMGN1 and HMGN2, is high in all tissues but progressively drops throughout the entire embryo as development and cellular differentiation proceed. Such a developmental drop in HMGN levels does not occur, however, in continuously renewing cell types such as the basal kidney epithelium where cell proliferation and differentiation are ongoing processes [57,84]. Together these observations suggest that during embryonic development there is an inverse correlation between the level of HMGN proteins and the differentiation state of cells. This idea is supported by experiments with tissue culture CGP 42112 which show that as cells differentiate their levels of HMGN drop [57,80] and that differentiation is inhibited when HMGNs are artificially overexpressed in cells [57,117]. Thus, proper cellular differentiation requires carefully regulated levels of HMGN expression. That it is the level, rather that the specific type, of HMGN proteins that is important for regulating differentiation is supported by the fact that homozygous knock-out mice are viable but exhibit various subtle abnormalities (see below), suggesting that during embryogenesis HMGN2 is able to partially compensated for the loss of HMGN1, probably because of a limited functional redundancy of these very similar proteins [19]. HMGN proteins primarily function by promoting the unfolding of higher-order chromatin structure and thereby enhancing transcription, replication and DNA repair from chromatin templates [24]. One of the principal mechanisms facilitating such unfolding is mediated by the ability of HMGN proteins to out-compete histone H1 for chromatin binding sites [29] (see Note added in proof). HMGN proteins are highly mobile within chromatin; nevertheless, more than 99% of HMGN1 molecules are bound to chromatin at any given moment, with residence times ranging from 4 to 25 s, thus allowing for a dynamic competition to exist between HMGN and H1 proteins in vivo[119]. The precise mechanism by which HMGN proteins mediate chromatin unfolding remains unclear, however, since ATP-dependent chromatin remodeling complexes are apparently not involved, at least not in vitro[67,130]. Another mechanism contributing to HMGN-induced structural changes in chromatin is the ability of these proteins to affect the levels of post-translational modification in the tails of histone proteins [88,89,123,161]. Members of the HMGN family bind exclusively and tightly to nucleosome core particles and stabilize their structure [27]. HMGNs are also the only non-histone proteins known to bind specifically inside the nucleosome between the gyres of DNA and the histone octamer core with the tail of histone H3 and histone H2B being involved in the interaction [24]. All HMGN proteins contain three important functional regions: a bipartite nuclear localization signal (NLS), a 30 amino acid long nucleosomal binding domain (NBD) and an acidic tail called the chromatin-unfolding domain (CHUD) [24]. Unlike the substrate binding domains of the other HMG families, the structure of the NBD of HMGN proteins has yet to be determined. Within the nucleus of interphase cells, HMGN1 and HMGN2 proteins are distributed in distinct foci, consistent with the demonstration that stretches of contiguous nucleosomes contain only one type of HMGN homodimer, either HMGN1 or HMGN2, and never mixtures of HMGN1/2 proteins [124,125]. In metaphase cells, however, the NBD of the HMGN proteins is inactivated and the proteins associate with chromatin only as monomers with low binding affinity. Neither do HMGN proteins form specific complexes in metaphase cells, demonstrating that the mode of binding of HMGNs to chromatin is cell cycle dependent [32].