This gene encodes a protein that belongs to the non-histone chromosomal high-mobility group (HMG) protein family. HMG proteins function as architectural factors and are essential components of the enhanceosome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. Identification of the deletion, amplification, and rearrangement of this gene that are associated with lipomas suggests a role in adipogenesis and mesenchymal differentiation. A gene knock-out study of the mouse counterpart demonstrated that this gene is involved in diet-induced obesity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[7]
The expression of HMGA2 in adult tissues is commonly associated with both malignant and benign tumor formation, as well as certain characteristic cancer-promoting mutations. Homologous proteins with highly conserved sequences are found in other mammalian species, including lab mice (Mus musculus).
HMGA2 contains three basic DNA-binding domains (AT-hooks) that cause the protein to bind to adenine-thymine (AT)-rich regions of nuclear DNA. HMGA2 does not directly promote or inhibit the transcription of any genes, but alters the structure of DNA and promotes the assembly of protein complexes that do regulate the transcription of genes. With few exceptions, HMGA2 is expressed in humans only during early development, and is reduced to undetectable or nearly undetectable levels of transcription in adult tissues.[8] The microRNAlet-7 is largely responsible for this time-dependent regulation of HMGA2.[9] The apparent function of HMGA2 in proliferation and differentiation of cells during development is supported by the observation that mice with mutant HMGA2 genes are unusually small (the pygmy or mini-mouse phenotype),[10] and genome-wide association studies linking HMGA2-associated SNPs to variation in human height.[11]
Let-7 inhibits production of specific proteins by complementary binding to their mRNA transcripts. The HMGA2 mature mRNA transcript contains seven regions complementary or nearly complementary to let-7 in its 3' untranslated region (UTR).[12] Let-7 expression is very low during early human development, which coincides with the greatest transcription of HMGA2. The time-dependent drop in HMGA2 expression is caused by a rise in let-7 expression.[9]
Heightened expression of HMGA2 is found in a variety of human cancers, but the precise mechanism by which HMGA2 contributes to the formation of cancer is unknown.[13][14] The same mutations that lead to pituitary adenomas in mice can be found in similar cancers in humans.[13] Its presence is associated with poor prognosis for the patient, but also with sensitization of the cancer cells to certain forms of cancer therapy.[15] To be specific, HMGA2-high cancers display an abnormally strong response to double strand breaks in DNA caused by radiation therapy and some forms of chemotherapy. Artificial addition of HMGA2 to some forms of cancer unresponsive to DNA damage cause them to respond to the treatment instead, although the mechanism by which this phenomenon occurs is also not understood.[15] However, the expression of HMGA2 is also associated with increased rates of metastasisinbreast cancer, and both metastasis and recurrence of squamous cell carcinoma. These properties are responsible for patients' poor prognoses. As with HMGA2's effects on the response to radiation and chemotherapy, the mechanism by which HMGA2 exerts these effects is unknown.[15]
A very common finding in HMGA2-high cancers is the under-expression of let-7.[16] This is not unexpected, given let-7's natural role in the regulation of HMGA2. However, many cancers are found with normal levels of let-7 that are also HMGA2 high. Many of these cancers express the normal HMGA2 protein, but the mature mRNA transcript is truncated, missing a portion of the 3'UTR that contains the critical let-7 complementary regions. Without these, let-7 is unable to bind to HMGA2 mRNA, and, thus, is unable to repress it. The truncated mRNAs may arise from a chromosomal translocation that results in loss of a portion of the HMGA2 gene.[12]
Overexpressed HMGA2 may play a role in the frequent repression of ERCC1 in cancers. The let-7a miRNA normally represses the HMGA2 gene, and in normal adult tissues, almost no HMGA2 protein is present.[17] (See also Let-7 microRNA precursor.) Reduction or absence of let-7a miRNA allows high expression of the HMGA2 protein. As shown by Borrmann et al.,[18] HMGA2 targets and modifies the chromatin architecture at the ERCC1 gene, reducing its expression. These authors noted that repression of ERCC1 (by HGMA2) can reduce DNA repair, leading to increased genome instability.
ERCC1 protein expression is reduced or absent in 84% to 100% of human colorectal cancers.[19][20] ERCC1 protein expression was also reduced in a diet-related mouse model of colon cancer.[21] As indicated in the ERCC1 article, however, two other epigenetic mechanisms of repression of ERCC1 also may have a role in reducing expression of ERCC1 (promoter DNA methylation and microRNA repression).
Overexpression of HMGA2 delayed the release of DNA-PKcs (needed for non-homologous end joining DNA repair) from double strand break sites. Overexpression of HMGA2 alone was sufficient to induce chromosomal aberrations, a hallmark of deficiency in NHEJ-mediated DNA repair. These properties implicate HMGA2 in the promotion of genome instability and tumorigenesis.[23] showed that
HMGA2 protein can cleave DNA containing apurinic/apyrimidinic (AP) sites (is an AP lyase). In addition, this protein also possesses the related 5’-deoxyribosyl phosphate (dRP) lyase activity. An interaction between human AP endonuclease 1 and HMGA2 in cancer cells has been demonstrated indicating that HMGA2 can be incorporated into the cellular base excision repair (BER) machinery. Increased expression of HMGA2 increased BER, and allowed cells with increased HMGA2 to be resistant to hydroxyurea, a chemotherapeutic agent for solid tumors.[24]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Ashar HR, Cherath L, Przybysz KM, Chada K (January 1996). "Genomic characterization of human HMGIC, a member of the accessory transcription factor family found at translocation breakpoints in lipomas". Genomics. 31 (2): 207–14. doi:10.1006/geno.1996.0033. PMID8824803.
^Ishwad CS, Shriver MD, Lassige DM, Ferrell RE (January 1997). "The high mobility group I-C gene (HMGI-C): polymorphism and genetic localization". Human Genetics. 99 (1): 103–5. doi:10.1007/s004390050320. PMID9003504. S2CID42615999.
^Meyer B, Loeschke S, Schultze A, Weigel T, Sandkamp M, Goldmann T, et al. (July 2007). "HMGA2 overexpression in non-small cell lung cancer". Molecular Carcinogenesis. 46 (7): 503–11. doi:10.1002/mc.20235. PMID17477356. S2CID30541611.
^ abcBoo LM, Lin HH, Chung V, Zhou B, Louie SG, O'Reilly MA, et al. (August 2005). "High mobility group A2 potentiates genotoxic stress in part through the modulation of basal and DNA damage-dependent phosphatidylinositol 3-kinase-related protein kinase activation". Cancer Research. 65 (15): 6622–30. doi:10.1158/0008-5472.CAN-05-0086. PMID16061642.
^Zha L, Wang Z, Tang W, Zhang N, Liao G, Huang Z (May 2012). "Genome-wide analysis of HMGA2 transcription factor binding sites by ChIP on chip in gastric carcinoma cells". Molecular and Cellular Biochemistry. 364 (1–2): 243–51. doi:10.1007/s11010-012-1224-z. PMID22246783. S2CID15777147.
Schoenmakers EF, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJ (August 1995). "Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours". Nature Genetics. 10 (4): 436–44. doi:10.1038/ng0895-436. PMID7670494. S2CID29935721.
Patel UA, Bandiera A, Manfioletti G, Giancotti V, Chau KY, Crane-Robinson C (May 1994). "Expression and cDNA cloning of human HMGI-C phosphoprotein". Biochemical and Biophysical Research Communications. 201 (1): 63–70. doi:10.1006/bbrc.1994.1669. PMID8198613.
Ashar HR, Cherath L, Przybysz KM, Chada K (January 1996). "Genomic characterization of human HMGIC, a member of the accessory transcription factor family found at translocation breakpoints in lipomas". Genomics. 31 (2): 207–14. doi:10.1006/geno.1996.0033. PMID8824803.
Ishwad CS, Shriver MD, Lassige DM, Ferrell RE (January 1997). "The high mobility group I-C gene (HMGI-C): polymorphism and genetic localization". Human Genetics. 99 (1): 103–5. doi:10.1007/s004390050320. PMID9003504. S2CID42615999.
Petit MM, Swarts S, Bridge JA, Van de Ven WJ (October 1998). "Expression of reciprocal fusion transcripts of the HMGIC and LPP genes in parosteal lipoma". Cancer Genetics and Cytogenetics. 106 (1): 18–23. doi:10.1016/S0165-4608(98)00038-7. PMID9772904.
Schoenmakers EF, Huysmans C, Van de Ven WJ (January 1999). "Allelic knockout of novel splice variants of human recombination repair gene RAD51B in t(12;14) uterine leiomyomas". Cancer Research. 59 (1): 19–23. PMID9892177.
