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

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.

HMGA1结构型转录因子（HMGA1 architectural transcription factor）是一种在绝大多数人类癌症中过表达的癌基因。HMGA1是核分子网络中高度连接的节点，其参与癌症发生发展的核心特征在于，可同时赋予细胞多重致癌效应，涵盖从整体染色质结构与基因表达修饰，直至关键细胞蛋白的直接功能异常等多个层面。值得关注的是，HMGA1还可调控DNA损伤修复通路。本研究中，我们提供了将HMGA1与非同源末端连接（Non-Homologous End Joining）DNA修复相关联的证据。我们证实HMGA1可与DNA依赖性蛋白激酶（DNA-PK）形成复合物并作为其底物。HMGA1能够增强连接酶IV（Ligase IV）的活性，并抵消组蛋白H1对DNA末端连接的抑制作用。此外，过表达HMGA1的乳腺癌细胞在诱导DNA双链断裂后展现出更快的修复恢复速率，且与更高的细胞存活率相关。上述数据表明，癌细胞对DNA损伤剂的耐药性可能部分归因于HMGA1的过表达，这也凸显了在筛选优质且有效的药物治疗方案时，考量HMGA1表达水平的重要性。