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Molecular Evaluation of Transformation‐Induced Methylation of the High Mobility Group A1 (HMGA1) Chromatin Binding Proteins
Author(s) -
Bufkin Kendra,
Nelson Ronald,
Deng Jaiyue,
Sumter Takita
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.877.19
Subject(s) - high mobility group , chromatin , methylation , transformation (genetics) , dna methylation , chemistry , dna binding protein , genetics , microbiology and biotechnology , biology , dna , gene , transcription factor , gene expression
Aberrant expression of high mobility group A1 ( hmga1) , resulting from inactivating defects in upstream tumor suppressor genes or upregulation of oncogenic transactivators, induces the initiation of cancer progression pathways. The protein products of hmga1, HMGA1a and HMGA1b, are characterized by the presence of three DNA‐binding motifs that possess a central RGR sequence and preferentially bind to the minor‐groove of AT‐rich stretches of target DNA. Importantly, R25 of the RGR sequence within the first DNA‐binding motif bears covalent modifications that may recruit or repel specific transcriptional regulators in cancer cells. Despite the implication of hmga1 and arginine methylation in oncogenic function, the role of epigenetic regulation of hmga1 by arginine methylation has not been evaluated. Here, we investigate the impact of R25 substitutions on HMGA1b binding DNA targets using fluorescence spectroscopy and functional cellular assays. R25 substitutions disrupt DNA binding to various targets and suppress HMGA1‐dependent oncogenic transformation. Together, our data reveals new potential anti‐cancer strategies by targeting HMGA1 protein methylation and downstream targets.