HMG chromosomal proteins in development and disease

Abstract

The high mobility group (HMG) proteins are a superfamily of abundant and ubiquitous nuclear proteins that bind to DNA and nucleosomes and induce structural changes in the chromatin fiber. They are important in chromatin dynamics and influence DNA processing in the context of chromatin. Results emerging from studies of human disease, genetically modified mice and cells with altered HMG expression indicate that the expression of the HMG proteins is developmentally regulated and that changes in HMG protein levels alter the cellular phenotype and can lead to developmental abnormalities and disease. Here, we focus on the biological function of HMG proteins and highlight their possible roles in cellular differentiation and in the etiology of various diseases.

Interaction between HMGA1a and the origin recognition complex creates site-specific replication origins

“…We used an HMGA1a mutant, HMGA1a(R3xG), in which glycines replaced the arginines (R28G, R69G, and R86G) of the AT-hook consensus motifs (GRP). This HMGA1a mutant shows a diffuse nuclear localization pattern (16). HeG2 cells expressing Orc6 and HMGA1a(R3xG)-BiFC proteins (93.6%) showed f luorescence complementation, and most Orc6/ HMGA1a complexes were now found in nucleoli (Fig.…”

“…Overexpression of HMGA1a can transcriptionally up-regulate cell cycle and growth regulators, i.e., cyclin A, p38 MAPK or N-myc (17). In addition, steady-state protein levels of HMGA1a are elevated in cancer cells with high proliferative potential (16) but decreased in differentiated cells. In contrast, deletion of one Hmga allele results in a pygmy phenotype in mice (15), and the expression of antisense RNA or a dominant-negative HMGA1a variant diminishes proliferation of tumor cells (17).…”

“…One member, HMGA1a, binds with high specificity to the minor groove of AT tracks and induces conformational changes (13). It is known as a structural nonhistone chromatin constituent that competes and antagonizes histone H1-mediated repression of genes (14), thus contributing to cell proliferation (15)(16)(17). However, no direct role in origin definition or DNA replication has been ascribed to HMGA proteins.…”

Micromechanical studies of mitotic chromosomes

“…Two small proteins that are likely to be important to chromatin folding are high-mobility-group (HMG) proteins, and the barrier-to-integration-factor (BAF-1) protein (Margalit et al 2007), which are present in mitotic chromosomes in numbers comparable to those of histones (Uchiyama et al 2005). HMG proteins are divided into three families with different functions (Hock et al 2007): HMGA proteins bind AT-rich DNA, HMGB proteins bend DNA (Thomas & Travers 2001), and HMGN proteins reorganize nucleosomes.…”

Architecture of the high mobility group nucleosomal protein 2-nucleosome complex as revealed by methyl-based NMR

“…HMGNs decompact chromatin condensed by the linker histone H1 (8), thereby enhancing transcription activity of the chromatin template. In addition, HMGNs affect DNA repair (9), chromatin remodeling (10), and the extent of histone modifications (11).…”