Tags

Type your tag names separated by a space and hit enter

Perturbation of RNA Polymerase I transcription machinery by ablation of HEATR1 triggers the RPL5/RPL11-MDM2-p53 ribosome biogenesis stress checkpoint pathway in human cells.
Cell Cycle. 2018; 17(1):92-101.CC

Abstract

Ribosome biogenesis is an energy consuming process which takes place mainly in the nucleolus. By producing ribosomes to fuel protein synthesis, it is tightly connected with cell growth and cell cycle control. Perturbation of ribosome biogenesis leads to the activation of p53 tumor suppressor protein promoting processes like cell cycle arrest, apoptosis or senescence. This ribosome biogenesis stress pathway activates p53 through sequestration of MDM2 by a subset of ribosomal proteins (RPs), thereby stabilizing p53. Here, we identify human HEATR1, as a nucleolar protein which positively regulates ribosomal RNA (rRNA) synthesis. Downregulation of HEATR1 resulted in cell cycle arrest in a manner dependent on p53. Moreover, depletion of HEATR1 also caused disruption of nucleolar structure and activated the ribosomal biogenesis stress pathway - RPL5 / RPL11 dependent stabilization and activation of p53. These findings reveal an important role for HEATR1 in ribosome biogenesis and further support the concept that perturbation of ribosome biosynthesis results in p53-dependent cell cycle checkpoint activation, with implications for human pathologies including cancer.

Authors+Show Affiliations

a Institute of Molecular and Translational Medicine , Faculty of Medicine and Dentistry , Palacky University , 779 00 Olomouc , Czech Republic.a Institute of Molecular and Translational Medicine , Faculty of Medicine and Dentistry , Palacky University , 779 00 Olomouc , Czech Republic.a Institute of Molecular and Translational Medicine , Faculty of Medicine and Dentistry , Palacky University , 779 00 Olomouc , Czech Republic.a Institute of Molecular and Translational Medicine , Faculty of Medicine and Dentistry , Palacky University , 779 00 Olomouc , Czech Republic. b Genome Integrity Unit , Danish Cancer Society Research Center , DK-2100 Copenhagen , Denmark. c Department of Medical Biochemistry and Biophysics , Division of Genome Biology , Science for Life Laboratory , Karolinska Institute , 171 65 Stockholm , Sweden.a Institute of Molecular and Translational Medicine , Faculty of Medicine and Dentistry , Palacky University , 779 00 Olomouc , Czech Republic.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29143558

Citation

Turi, Zsofia, et al. "Perturbation of RNA Polymerase I Transcription Machinery By Ablation of HEATR1 Triggers the RPL5/RPL11-MDM2-p53 Ribosome Biogenesis Stress Checkpoint Pathway in Human Cells." Cell Cycle (Georgetown, Tex.), vol. 17, no. 1, 2018, pp. 92-101.
Turi Z, Senkyrikova M, Mistrik M, et al. Perturbation of RNA Polymerase I transcription machinery by ablation of HEATR1 triggers the RPL5/RPL11-MDM2-p53 ribosome biogenesis stress checkpoint pathway in human cells. Cell Cycle. 2018;17(1):92-101.
Turi, Z., Senkyrikova, M., Mistrik, M., Bartek, J., & Moudry, P. (2018). Perturbation of RNA Polymerase I transcription machinery by ablation of HEATR1 triggers the RPL5/RPL11-MDM2-p53 ribosome biogenesis stress checkpoint pathway in human cells. Cell Cycle (Georgetown, Tex.), 17(1), 92-101. https://doi.org/10.1080/15384101.2017.1403685
Turi Z, et al. Perturbation of RNA Polymerase I Transcription Machinery By Ablation of HEATR1 Triggers the RPL5/RPL11-MDM2-p53 Ribosome Biogenesis Stress Checkpoint Pathway in Human Cells. Cell Cycle. 2018;17(1):92-101. PubMed PMID: 29143558.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Perturbation of RNA Polymerase I transcription machinery by ablation of HEATR1 triggers the RPL5/RPL11-MDM2-p53 ribosome biogenesis stress checkpoint pathway in human cells. AU - Turi,Zsofia, AU - Senkyrikova,Marketa, AU - Mistrik,Martin, AU - Bartek,Jiri, AU - Moudry,Pavel, Y1 - 2017/12/10/ PY - 2017/11/17/pubmed PY - 2019/9/7/medline PY - 2017/11/17/entrez KW - HEATR1 KW - cancer KW - p53 KW - ribosome biogenesis KW - ribosome biogenesis stress SP - 92 EP - 101 JF - Cell cycle (Georgetown, Tex.) JO - Cell Cycle VL - 17 IS - 1 N2 - Ribosome biogenesis is an energy consuming process which takes place mainly in the nucleolus. By producing ribosomes to fuel protein synthesis, it is tightly connected with cell growth and cell cycle control. Perturbation of ribosome biogenesis leads to the activation of p53 tumor suppressor protein promoting processes like cell cycle arrest, apoptosis or senescence. This ribosome biogenesis stress pathway activates p53 through sequestration of MDM2 by a subset of ribosomal proteins (RPs), thereby stabilizing p53. Here, we identify human HEATR1, as a nucleolar protein which positively regulates ribosomal RNA (rRNA) synthesis. Downregulation of HEATR1 resulted in cell cycle arrest in a manner dependent on p53. Moreover, depletion of HEATR1 also caused disruption of nucleolar structure and activated the ribosomal biogenesis stress pathway - RPL5 / RPL11 dependent stabilization and activation of p53. These findings reveal an important role for HEATR1 in ribosome biogenesis and further support the concept that perturbation of ribosome biosynthesis results in p53-dependent cell cycle checkpoint activation, with implications for human pathologies including cancer. SN - 1551-4005 UR - https://www.unboundmedicine.com/medline/citation/29143558/Perturbation_of_RNA_Polymerase_I_transcription_machinery_by_ablation_of_HEATR1_triggers_the_RPL5/RPL11_MDM2_p53_ribosome_biogenesis_stress_checkpoint_pathway_in_human_cells_ L2 - http://www.tandfonline.com/doi/full/10.1080/15384101.2017.1403685 DB - PRIME DP - Unbound Medicine ER -