title: Phosphorylation regulates the Star-PAP-PIPKIα interaction and directs specificity toward mRNA targets.
abstract: Star-PAP is a nuclear non-canonical poly(A) polymerase (PAP) that shows specificity toward mRNA targets. Star-PAP activity is stimulated by lipid messenger phosphatidyl inositol 4,5 bisphoshate (PI4,5P2) and is regulated by the associated Type I phosphatidylinositol-4-phosphate 5-kinase that synthesizes PI4,5P2 as well as protein kinases. These associated kinases act as coactivators of Star-PAP that regulates its activity and specificity toward mRNAs, yet the mechanism of control of these interactions are not defined. We identified a phosphorylated residue (serine 6, S6) on Star-PAP in the zinc finger region, the domain required for PIPKIα interaction. We show that S6 is phosphorylated by CKIα within the nucleus which is required for Star-PAP nuclear retention and interaction with PIPKIα. Unlike the CKIα mediated phosphorylation at the catalytic domain, Star-PAP S6 phosphorylation is insensitive to oxidative stress suggesting a signal mediated regulation of CKIα activity. S6 phosphorylation together with coactivator PIPKIα controlled select subset of Star-PAP target messages by regulating Star-PAP-mRNA association. Our results establish a novel role for phosphorylation in determining Star-PAP target mRNA specificity and regulation of 3'-end processing.
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud Post, Poojappura, Trivandrum 695014, India.
authors.forename: Nimmy
authors.initials: N
authors.lastname: Mohan
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud Post, Poojappura, Trivandrum 695014, India.
authors.forename: A P
authors.initials: AP
authors.lastname: Sudheesh
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud Post, Poojappura, Trivandrum 695014, India.
authors.forename: Nimmy
authors.initials: N
authors.lastname: Francis
authors.affiliation: School of Medicine and Public Health, University of Wisconsin-Madison, WI 53706, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Anderson
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud Post, Poojappura, Trivandrum 695014, India laishram@rgcb.res.in.
authors.forename: Rakesh S
authors.initials: RS
authors.lastname: Laishram
mesh_terms: D047389:Casein Kinase I / Q000378:metabolism; D002467:Cell Nucleus / Q000201:enzymology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009713:Nucleotidyltransferases; D018384:Oxidative Stress; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011062:Polynucleotide Adenylyltransferase / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D026721:RNA 3' End Processing; D012333:RNA, Messenger / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D016335:Zinc Fingers
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D012333:RNA, Messenger; D012694:Serine; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D047389:Casein Kinase I; D009713:Nucleotidyltransferases; C586325:TUT1 protein, human; D011062:Polynucleotide Adenylyltransferase