The Architectural Chromatin Factor High Mobility Group A1 Enhances DNA Ligase IV Activity Influencing DNA Repair

The HMGA1architectural transcription factor is an oncogene overexpressed in the vast majority of human cancers. HMGA1is a highly connected node in the nuclear molecular network and the key aspect of HMGA1involvement in cancer development is that HMGA1simultaneously 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, HMGA1also modulates DNA damage repair pathways. In this work, we provide evidences linking HMGA1with Non-Homologous End JoiningDNA repair. We show that HMGA1is in complex with and is a substrate for DNA-PK. HMGA1enhances Ligase IV activity and it counteracts the repressive histone H1activity towards DNA ends ligation. Moreover, breast cancer cells overexpressing HMGA1show 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 HMGA1overexpression thus highlighting the relevance of considering HMGA1expression levels in the selection of valuable and effective pharmacological regimens.