NBS1 interacts with HP1 to ensure genome integrity
| Autor: | Jacopo Albanesi, Laura Ciapponi, Fabio Polticelli, Simona Cugusi, Giovanni Cenci, Valentina Brandi, Francesca Cipressa, Antonio Antoccia, Alessandra di Masi, Maria Lina Moroni, Rosa Pennisi, Giuseppe Bosso, Fioranna Renda |
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| Přispěvatelé: | Bosso, G, Cipressa, F, Moroni, Ml, Pennisi, R, Albanesi, J, Brandi, V, Cugusi, S, Renda, F, Ciapponi, L, Polticelli, F, Antoccia, A, di Masi, A, Cenci, G |
| Rok vydání: | 2019 |
| Předmět: |
Male
Cancer Research Chromosomal Proteins Non-Histone DNA damage Genome Insect Immunology Diseases Cell Cycle Proteins Biology NBS1 Article Chromosomes Genomic Instability NBS1 HP1 Drosophila genome stability Cellular and Molecular Neuroscience medicine Animals Drosophila Proteins Humans lcsh:QH573-671 Nijmegen Breakage Syndrome Endodeoxyribonucleases lcsh:Cytology HP1 DNA replication Nuclear Proteins Cell Biology Fibroblasts medicine.disease Telomere Chromatin Cell biology Drosophila melanogaster Exodeoxyribonucleases Gene Expression Regulation MRN complex Chromobox Protein Homolog 5 Rad50 Mutation embryonic structures Female Drosophila Heterochromatin protein 1 genome stability Nijmegen breakage syndrome DNA Damage |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 10, Iss 12, Pp 1-15 (2019) |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-019-2185-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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