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NBS1 interacts with HP1 to ensure genome integrity
- Source :
- Cell Death & Disease, Cell Death and Disease, Vol 10, Iss 12, Pp 1-15 (2019)
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 20414889
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Cell Death & Disease
- Accession number :
- edsair.doi.dedup.....8025b37094aad08bee62e6d3710ca493