1. The Architectural Chromatin Factor High Mobility Group A1 Enhances DNA Ligase IV Activity Influencing DNA Repair.
- Author
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Pellarin I, Arnoldo L, Costantini S, Pegoraro S, Ros G, Penzo C, Triolo G, Demarchi F, Sgarra R, Vindigni A, and Manfioletti G
- Subjects
- Cell Line, Tumor, Chromatin metabolism, Chromatography, High Pressure Liquid, Comet Assay, HMGA1a Protein genetics, HMGA2 Protein genetics, HMGA2 Protein metabolism, Histones metabolism, Humans, Ku Autoantigen metabolism, MCF-7 Cells, Microscopy, Fluorescence, Phosphorylation, Recombinant Proteins biosynthesis, Recombinant Proteins chemistry, Recombinant Proteins isolation & purification, Substrate Specificity, Chromatin chemistry, DNA Ligase ATP metabolism, DNA Repair, HMGA1a Protein metabolism
- Abstract
The HMGA1 architectural transcription factor is an oncogene overexpressed in the vast majority of human cancers. HMGA1 is a highly connected node in the nuclear molecular network and the key aspect of HMGA1 involvement in cancer development is that HMGA1 simultaneously confers cells multiple oncogenic hits, ranging from global chromatin structural and gene expression modifications up to the direct functional alterations of key cellular proteins. Interestingly, HMGA1 also modulates DNA damage repair pathways. In this work, we provide evidences linking HMGA1 with Non-Homologous End Joining DNA repair. We show that HMGA1 is in complex with and is a substrate for DNA-PK. HMGA1 enhances Ligase IV activity and it counteracts the repressive histone H1 activity towards DNA ends ligation. Moreover, breast cancer cells overexpressing HMGA1 show a faster recovery upon induction of DNA double-strand breaks, which is associated with a higher survival. These data suggest that resistance to DNA-damaging agents in cancer cells could be partially attributed to HMGA1 overexpression thus highlighting the relevance of considering HMGA1 expression levels in the selection of valuable and effective pharmacological regimens., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
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