期刊
NUCLEIC ACIDS RESEARCH
卷 50, 期 2, 页码 803-819出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab1263
关键词
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资金
- NIH [R01-GM134021, R35-GM126945]
- NCI Cancer Center Support Grant [P30 CA08748]
- Cycle for Survival
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
Expression of fission yeast Pho1 acid phosphatase is repressed by transcription of an upstream prt lncRNA and regulated by inositol pyrophosphate kinase Asp1. The 14-3-3 protein Rad24 is identified as a regulator of phosphate homeostasis. Mutations in Rad24 lead to increased Pho1 activity, and epistasis analysis reveals specific factors involved in this regulation. This study uncovers a new role for 14-3-3 protein as an inhibitor of RNA processing.
Expression of fission yeast Pho1 acid phosphatase is repressed under phosphate-replete conditions by transcription of an upstream prt lncRNA that interferes with the pho1 mRNA promoter. lncRNA control of pho1 mRNA synthesis is influenced by inositol pyrophosphate (IPP) kinase Asp1, deletion of which results in pho1 hyper-repression. A forward genetic screen for ADS (Asp1 Deletion Suppressor) mutations identified the 14-3-3 protein Rad24 as a governor of phosphate homeostasis. Production of full-length interfering prt lncRNA was squelched in rad24 Delta cells, concomitant with increased production of pho1 mRNA and increased Pho1 activity, while shorter precociously terminated non-interfering prt transcripts persisted. Epistasis analysis showed that pho1 de-repression by rad24 Delta depends on: (i) 3 '-processing and transcription termination factors CPF, Pin1, and Rhn1; and (ii) Threonine-4 of the Pol2 CTD. Combining rad24 Delta with the IPP pyrophosphatase-dead asp1-H397A allele caused a severe synthetic growth defect that was ameliorated by loss-of-function mutations in CPF, Pin1, and Rhn1, and by CTD phospho-site mutations T4A and Y1F. Rad24 function in repressing pho1 was effaced by mutation of its phosphate-binding pocket. Our findings instate a new role for a 14-3-3 protein as an antagonist of precocious RNA 3 '-processing/termination.
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