Insights into telomeric G-quadruplex DNA recognition by HMGB1 protein
Insights into telomeric G-quadruplex DNA recognition by HMGB1 protein
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DOI：
10.1093/nar/gkz727
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发表时间：
2019-10-10
影响因子：
14.9
通讯作者：
Pagano, Bruno
中科院分区：
文献类型：
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作者：
Amato, Jussara;Cerofolini, Linda;Pagano, Bruno
HMGB 1是一种普遍存在的非组蛋白，其生物学效应依赖于其表达和亚细胞定位。在细胞核内，HMGB 1参与许多DNA事件，如DNA修复，转录和端粒维持。据报道，HMGB 1优先结合弯曲的DNA以及非规范的DNA结构，如4路连接，最近，G-四链体。这些是参与重要细胞过程（包括端粒维持）的核酸的四链构象。在这个框架下，G-四链体识别特定的蛋白质代表了一个关键事件，调节生理或病理途径。在此，为了深入了解端粒G-四链体DNA识别HMGB 1，我们进行了详细的生物物理研究，辅以生物分析。所获得的结果提供了有关相互作用的分子决定因素的信息，并表明人类端粒G-四链体DNA的结构变异性可能对HMGB 1识别具有重要意义。生物学数据确定HMGB 1作为端粒相关蛋白在端粒酶阳性和阴性肿瘤细胞中，并表明HMGB 1基因沉默在这些细胞中诱导端粒DNA损伤灶。总而言之，这些发现提供了对HMGB 1端粒G-四链体识别的更深入理解，并表明这种蛋白实际上可能代表癌症治疗的新靶点。
HMGB1 is a ubiquitous non-histone protein, which biological effects depend on its expression and subcellular location. Inside the nucleus, HMGB1 is engaged in many DNA events such as DNA repair, transcription and telomere maintenance. HMGB1 has been reported to bind preferentially to bent DNA as well as to noncanonical DNA structures like 4-way junctions and, more recently, to G-quadruplexes. These are four-stranded conformations of nucleic acids involved in important cellular processes, including telomere maintenance. In this frame, G-quadruplex recognition by specific proteins represents a key event to modulate physiological or pathological pathways. Herein, to get insights into the telomeric G-quadruplex DNA recognition by HMGB1, we performed detailed biophysical studies complemented with biological analyses. The obtained results provided information about the molecular determinants for the interaction and showed that the structural variability of human telomeric G-quadruplex DNA may have significant implications in HMGB1 recognition. The biological data identified HMGB1 as a telomere-associated protein in both telomerase-positive and -negative tumor cells and showed that HMGB1 gene silencing in such cells induces telomere DNA damage foci. Altogether, these findings provide a deeper understanding of telomeric G-quadruplex recognition by HMGB1 and suggest that this protein could actually represent a new target for cancer therapy.