Heterochromatin Protein 1 (HP1) and the Mre11-Rad50-Nbs1 (MRN) complex are conserved factors that play crucial role in genome stability and integrity. Despite their involvement in overlapping cellular functions, ranging from chromatin organization, telomere maintenance to DNA replication and repair, a tight functional relationship between HP1 and the MRN complex has never been elucidated. Here we show that the Drosophila HP1a protein binds to the MRN complex through its chromoshadow domain (CSD). In addition, loss of any of the MRN members reduces HP1a levels indicating that the MRN complex acts as regulator of HP1a stability. Moreover, overexpression of HP1a in nbs (but not in rad50 or mre11) mutant cells drastically reduces DNA damage associated with the loss of Nbs suggesting that HP1a and Nbs work in concert to maintain chromosome integrity in flies. We have also found that human HP1α and NBS1 interact with each other and that, similarly to Drosophila, siRNA-mediated inhibition of NBS1 reduces HP1α levels in human cultured cells. Surprisingly, fibroblasts from Nijmegen Breakage Syndrome (NBS) patients, carrying the 657del5 hypomorphic mutation in NBS1 and expressing the p26 and p70 NBS1 fragments, accumulate HP1α indicating that, differently from NBS1 knockout cells, the presence of truncated NBS1 extends HP1α turnover and/or promotes its stability. Remarkably, an siRNA-mediated reduction of HP1α in NBS fibroblasts decreases the hypersensitivity to irradiation, a characteristic of the NBS syndrome. Overall, our data provide an unanticipated evidence of a close interaction between HP1 and NBS1 that is essential for genome stability and point up HP1α as a potential target to counteract chromosome instability in NBS patient cells.

中文翻译：

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NBS1与HP1相互作用以确保基因组完整性。

异染色质蛋白1（HP1）和Mre11-Rad50-Nbs1（MRN）复合物是在基因组稳定性和完整性中起关键作用的保守因子。尽管它们参与了重叠的细胞功能，从染色质组织，端粒维护到DNA复制和修复，但HP1和MRN复合物之间的紧密功能关系从未阐明。在这里，我们显示果蝇HP1a蛋白通过其色影域（CSD）与MRN复合物结合。此外，任何MRN成员的丢失都会降低HP1a的水平，这表明MRN复合物可作为HP1a稳定性的调节剂。而且，在nbs（而不是rad50或mre11）突变细胞中过高表达HP1a可以大大减少与Nbs丢失相关的DNA损伤，这表明HP1a和Nbs协同工作以维持果蝇的染色体完整性。我们还发现，人HP1α和NBS1彼此相互作用，并且与果蝇相似，siRNA介导的NBS1抑制作用降低了人培养细胞中的HP1α水平。出乎意料的是，来自奈梅亨断裂综合症（NBS）患者的成纤维细胞在NBS1中携带657del5亚型突变并表达p26和p70 NBS1片段，积累HP1α，这表明与NBS1基因敲除细胞不同，截短的NBS1的存在延长了HP1α的更新和/或增强其稳定性。值得注意的是，siRNA介导的NBS成纤维细胞中HP1α的减少降低了对辐射的超敏性，NBS综合征的特征。总体而言，我们的数据为HP1和NBS1之间的紧密相互作用提供了意料之外的证据，这对于基因组稳定性至关重要，并指出HP1α是抵消NBS患者细胞中染色体不稳定的潜在靶标。