title: The Architectural Chromatin Factor High Mobility Group A1 Enhances DNA Ligase IV Activity Influencing DNA Repair.
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.
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Pellarin
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Arnoldo
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Costantini
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pegoraro
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Ros
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Penzo
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Triolo
authors.affiliation: Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), AREA Science Park, Trieste, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Demarchi
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Sgarra
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vindigni
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Guidalberto
authors.initials: G
authors.lastname: Manfioletti
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D020552:Comet Assay; D000072481:DNA Ligase ATP / Q000378:metabolism*; D004260:DNA Repair; D025741:HMGA1a Protein / Q000235:genetics / Q000378:metabolism*; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D000072200:Ku Autoantigen / Q000378:metabolism; D061986:MCF-7 Cells; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D013379:Substrate Specificity
chemical_list: D002843:Chromatin; D025743:HMGA2 Protein; D006657:Histones; D011994:Recombinant Proteins; D025741:HMGA1a Protein; D000072200:Ku Autoantigen; D000072481:DNA Ligase ATP