BTG proteins in cellular proliferation, differentiation, and mRNA turnover

• Applicant: Professor Dr. Georg Stoecklin
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry ; Cell Biology
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 283844389

Final Report Abstract

The control of messenger (m)RNA stability is an important post-transcriptional regulatory step that allow fast changes in protein expression. The CCR4-NOT complex serves as a major regulator of mRNA decay by the shortening the poly(A) tail of mRNA via its two catalytic subunits, the deadenylases CCR4 and CAF1. In this ANR-DFG project, the labs of Bertrand Séraphin (IGBMC, Illkirch, France) and Georg Stoecklin (Heidelberg University, Germany) analyzed how the CAF1 deadenylase activity is regulated by direct modification of CAF1 and by its partner, BTG2, a protein that has antiproliferative properties. We have shown that acetylation of CAF1 by p300 and CPB acetyltransferases accelerates mRNA decay. Of note, we observed a reduction of p300 and CPB expression during adipocyte differentiation and concomitantly a global stabilization of mRNA, uncovering that cellular differentiation leads to mRNA stabilization. Interestingly, acetylation of CAF1 stabilizes its interaction with the factor BTG2. We further uncovered that BTG2 interacts also the main cytoplasmic poly(A)-binding protein (PABPC1), thereby recruiting mRNAs for deadenylation to the CCR4-NOT complex. We could demonstrate that the interactions of BTG2 with CAF1 and PABPC1 are sufficient and necessary for BTG2 to stimulate deadenylation, and that this mechanism is necessary for the antiproliferative properties of BTG2. We also obtained detailed structural insight into the mode by which the BoxC motif in BTG2 interacts with the firs RNA-recognition motif (RRM) of PABPC1. Our transcriptome-wide studies on mRNAs that are preferentially targeted by BTG2 identified targets that are responsible for the antiproliferative activity of BTG2. Finally, we identified an additional RNA-binding protein that associates with BTG2 and appears to mediate preferential decay of specific targets. This project illustrates how the regulation of mRNA stability can impact cell proliferation and therefore potentially the development of cancers.

Publications

• Acetylation-Dependent Control of Global Poly-A RNA Degradation by CBP/p300 and HDAC1/2. Mol Cell 2016;63:927-38
  Sharma S, Poetz F, Bruer M, Ly-Hartig TBN, Schott J, Séraphin B, Stoecklin G
  
• BTG2 bridges PABPC1 RNA-binding domains and CAF1 deadenylase to control cell proliferation. Nat Commun. 2016;7:10811
  Stupfler B, Birck C, Séraphin B, Mauxion F
  
• A conserved motif in human BTG1 and BTG2 proteins mediates interaction with the poly(A) binding protein PABPC1 to stimulate mRNA deadenylation. RNA Biol 2021 Jun 1;1-16
  Amine H, Ripin N, Sharma S, Stoecklin G, Allain FH, Séraphin B, Mauxion F