RNA polymerase II transcription is required for human papillomavirus type 16 E7- and hydroxyurea-induced centriole overduplication.
Aberrant centrosome numbers are detected in virtually all human cancers where they can contribute to chromosomal instability by promoting mitotic spindle abnormalities. Despite their widespread occurrence, the molecular mechanisms that underlie centrosome amplification are only beginning to emerge. Here, we present evidence for a novel regulatory circuit involved in centrosome overduplication that centers on RNA polymerase II (pol II). We found that human papillomavirus type 16 E7 (HPV-16 E7)- and hydroxyurea (HU)-induced centriole overduplication are abrogated by alpha-amanitin, a potent and specific RNA pol II inhibitor. In contrast, normal centriole duplication proceeded undisturbed in alpha-amanitin-treated cells. Centriole overduplication was significantly reduced by siRNA-mediated knock down of CREB-binding protein (CBP), a transcriptional co-activator. We identified cyclin A2 as a key transcriptional target of RNA pol II during HU-induced centriole overduplication. Collectively, our results show that ongoing RNA pol II transcription is required for centriole overduplication whereas it may be dispensable for normal centriole duplication. Given that many chemotherapeutic agents function through inhibition of transcription, our results may help to develop strategies to target centrosome-mediated chromosomal instability for cancer therapy and prevention.
Duensing
A
A
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. duensing@pitt.edu
Liu
Y
Y
Spardy
N
N
Bartoli
K
K
Tseng
M
M
Kwon
J-A
JA
Teng
X
X
Duensing
S
S
D000546:Amanitins / Q000494:pharmacology; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018385:Centrosome / Q000502:physiology*; D019925:Cyclin A / Q000378:metabolism; D056751:Cyclin A2; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D009856:Oncogene Proteins, Viral / Q000494:pharmacology*; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D050725:Papillomavirus E7 Proteins; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000546:Amanitins; C503721:CCNA2 protein, human; D019925:Cyclin A; D056751:Cyclin A2; D004791:Enzyme Inhibitors; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D034741:RNA, Small Interfering; C059731:oncogene protein E7, Human papillomavirus type 16; D050882:CREB-Binding Protein; D012319:RNA Polymerase II; D006918:Hydroxyurea