This gene encodes a non-histone chromatin protein involved in many cellular processes, including regulation of inducible gene transcription, DNA replication,heterochromatin organization,integration of retroviruses into chromosomes, and the metastatic progression of cancer cells.
HMGA1 proteins are quite small (~10-12 kDa) and basic molecules, and consist of threeAT-hooks with the RGRP (Arg-Gly-Arg-Pro) coremotif, a novelcross-linking domain located between the second and third AT-hook, and aC-terminal acidic tail characteristic for theHMG family comprising HMGA, HMGB and HMGN proteins.
HMGA1-GFP fusion proteins are highly dynamic in vivo (determined usingFRAP analysis), but in contrast also show nanomolar affinity to AT-rich DNA in vitro (determined biochemically), which might be explained due to the extensivepost-transcriptional modifications in vivo. HMGA1 preferentially binds to the minor groove of AT-rich regions in double-stranded DNA using its AT-hooks. It has little secondary structure in solution but assumes distinct conformations when bound to substrates such as DNA or other proteins. HMGA1 proteins have high amounts of diverseposttranslational modifications and are located mainly in the nucleus, especially in heterochromatin, but also in mitochondria and the cytoplasm.
Recently it has been shown that HMGA1 proteins, HMGA1a and HMGA1b, can cross-link DNA fibersin vitro and can induce chromatin clusteringin vivo suggesting a structural role of HMGA1 proteins in heterochromatin organization.[7]
At least seven transcript variants encoding two different isoforms (HMGA1a, HMGA1b) have been found for this gene.[8] The splice variant HMGA1c with only two AT hooks and no acidic tail is in discussion to be a real member of the HMGA family.
Mice lacking their variant ofHMGA1, i.e.,Hmga1-/- mice, arediabetic, show a cardiac hypertrophy and express low levels of theinsulin receptor.[9]
^Reeves R, Beckerbauer L (May 2001). "HMGI/Y proteins: flexible regulators of transcription and chromatin structure".Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression.1519 (1–2):13–29.doi:10.1016/S0167-4781(01)00215-9.PMID11406267.
Van Maele B, Debyser Z (2005). "HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral proteins".AIDS Reviews.7 (1):26–43.PMID15875659.
Karlson JR, Mørk E, Holtlund J, Laland SG, Lund T (Feb 1989). "The amino acid sequence of the chromosomal protein HMG-Y, its relation to HMG-I and possible domains for the preferential binding of the proteins to stretches of A-T base pairs".Biochemical and Biophysical Research Communications.158 (3):646–51.doi:10.1016/0006-291X(89)92770-8.PMID2920035.
Lund T, Dahl KH, Mørk E, Holtlund J, Laland SG (Jul 1987). "The human chromosomal protein HMG I contains two identical palindrome amino acid sequences".Biochemical and Biophysical Research Communications.146 (2):725–30.doi:10.1016/0006-291X(87)90589-4.PMID3619901.
Huth JR, Bewley CA, Nissen MS, Evans JN, Reeves R, Gronenborn AM, Clore GM (Aug 1997). "The solution structure of an HMG-I(Y)-DNA complex defines a new architectural minor groove binding motif".Nature Structural Biology.4 (8):657–65.doi:10.1038/nsb0897-657.PMID9253416.S2CID2183841.
Chiappetta G, Tallini G, De Biasio MC, Manfioletti G, Martinez-Tello FJ, Pentimalli F, de Nigris F, Mastro A, Botti G, Fedele M, Berger N, Santoro M, Giancotti V, Fusco A (Sep 1998). "Detection of high mobility group I HMGI(Y) protein in the diagnosis of thyroid tumors: HMGI(Y) expression represents a potential diagnostic indicator of carcinoma".Cancer Research.58 (18):4193–8.PMID9751634.
