Nucleolar repression facilitates initiation and maintenance of senescence.
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.
a Molecular Oncology Department ; Moffitt Cancer Center ; Tampa , FL USA.
Leixiang
L
Yang
a Molecular Oncology Department ; Moffitt Cancer Center ; Tampa , FL USA.
Tanjing
T
Song
a Molecular Oncology Department ; Moffitt Cancer Center ; Tampa , FL USA.
Lihong
L
Chen
b Women's Oncology ; Moffitt Cancer Center ; Tampa , FL USA.
Hatem
H
Soliman
a Molecular Oncology Department ; Moffitt Cancer Center ; Tampa , FL USA.
Jiandong
J
Chen
D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004275:DNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D006570:Heterochromatin / Q000737:chemistry* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012318:RNA Polymerase I / Q000235:genetics / Q000378:metabolism; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000092468:Bromodomain Containing Proteins
D002868:Chromosomal Proteins, Non-Histone; D004275:DNA, Ribosomal; D050687:E2F1 Transcription Factor; D006570:Heterochromatin; D006657:Histones; D008780:Methyltransferases; D009687:Nuclear Proteins; D012318:RNA Polymerase I; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins; D056564:Sirtuin 1; C436708:BAZ2A protein, human; D000092468:Bromodomain Containing Proteins; C493753:E2F1 protein, human; C529371:RRP8 protein, human; C447939:SIRT1 protein, human
NML; chemotherapy; heterochromatin; nucleolus; p53; rDNA; senescence