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Nucleolar repression facilitates initiation and maintenance of senescence
- Publication Year :
- 2015
- Publisher :
- Taylor & Francis, 2015.
-
Abstract
- Tumor cells with defective apoptosis pathways often respond to chemotherapy by entering irreversible cell cycle arrest with features of senescence. However, rare cells can bypass entry to senescence, or re-enter cell cycle from a senescent state. Deficiency in senescence induction and maintenance may contribute to treatment resistance and early relapse after therapy. Senescence involves epigenetic silencing of cell cycle genes and reduced rRNA transcription. We found that senescence-inducing treatments such as DNA damage and RNA polymerase I inhibition stimulate the binding between the nucleolar protein NML (nucleomethylin) and SirT1. The NML complex promotes rDNA heterochromatin formation and represses rRNA transcription. Depletion of NML reduced the levels of H3K9Me3 and H3K27Me3 heterochromatin markers on rDNA and E2F1 target promoters in senescent cells, increased rRNA transcription, and increased the frequency of cell cycle re-entry. Depletion of the nucleolar transcription repressor factor TIP5 also promoted escape from senescence. Furthermore, tumor tissue staining showed that breast tumors without detectable nucleolar NML expression had poor survival. The results suggest that efficient regulation of nucleolar rDNA transcription facilitates the maintenance of irreversible cell cycle arrest in senescent cells. Deficiency in nucleolar transcription repression may accelerate tumor relapse after chemotherapy.
- Subjects :
- Senescence
Male
Transcription, Genetic
Chromosomal Proteins, Non-Histone
Apoptosis
Breast Neoplasms
Biology
DNA, Ribosomal
Epigenesis, Genetic
Histones
Sirtuin 1
RNA Polymerase I
Cell Line, Tumor
Heterochromatin
E2F1
Humans
RDNA heterochromatin
Promoter Regions, Genetic
Molecular Biology
Cellular Senescence
Nuclear Proteins
RNA-Binding Proteins
E2F1 Transcription Factor
Promoter
Cell Biology
Cell Cycle Checkpoints
Methyltransferases
Cell cycle
Chromatin Assembly and Disassembly
RRNA transcription
Urinary Bladder Neoplasms
RNA, Ribosomal
Cancer research
Female
Cell aging
Cell Nucleolus
Developmental Biology
Reports
Protein Binding
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....5a53610213698321edbba4f9465ba381