PAF1, a Molecular Regulator of Promoter-Proximal Pausing by RNA Polymerase II.
The control of promoter-proximal pausing and the release of RNA polymerase II (Pol II) is a widely used mechanism for regulating gene expression in metazoans, especially for genes that respond to environmental and developmental cues. Here, we identify that Pol-II-associated factor 1 (PAF1) possesses an evolutionarily conserved function in metazoans in the regulation of promoter-proximal pausing. Reduction in PAF1 levels leads to an increased release of paused Pol II into gene bodies at thousands of genes. PAF1 depletion results in increased nascent and mature transcripts and increased levels of phosphorylation of Pol II's C-terminal domain on serine 2 (Ser2P). These changes can be explained by the recruitment of the Ser2P kinase super elongation complex (SEC) effecting increased release of paused Pol II into productive elongation, thus establishing PAF1 as a regulator of promoter-proximal pausing by Pol II.
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, IL 60611, USA.
Fei Xavier
FX
Chen
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, IL 60611, USA.
Ashley R
AR
Woodfin
Department of Human Genetics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1501 NW 10(th) Avenue, Miami, FL 33136, USA.
Alessandro
A
Gardini
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, IL 60611, USA.
Ryan A
RA
Rickels
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, IL 60611, USA.
Stacy A
SA
Marshall
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, IL 60611, USA.
Edwin R
ER
Smith
Department of Human Genetics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1501 NW 10(th) Avenue, Miami, FL 33136, USA.
Ramin
R
Shiekhattar
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, IL 60611, USA; Stowers Institute for Medical Research, 1000 East 50(th) Street, Kansas City, MO 64110, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 320 E. Superior Street, Chicago, IL 60611, USA. Electronic address: ash@northwestern.edu.
Ali
A
Shilatifard
D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D006657:Histones / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D054875:Ubiquitination
D029721:Drosophila Proteins; D006657:Histones; D009687:Nuclear Proteins; C501972:PAF1 protein, human; D014157:Transcription Factors; C508976:atms protein, Drosophila; D012319:RNA Polymerase II