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Eukaryotic cells AND Nuclear receptors

09/30/2011

Translational Co-Regulation of 5’TOP mRNAs by TIA-1 and TIAR

Christian Kroun Damgaard and Jens Lykke-Andersen

  Eukaryotic cells respond to nutrient deprivation by halting the energetically demanding processes of ribosome biosynthesis, and redirecting resources to the translation of other, essential genes. Here, Damgaard and Lykke-Andersen identify the stress granule-associated RNA binding proteins, TIA-1 and TIAR, as the long sought-after factors responsible for this translational co-regulation of mRNAs according to nutrient conditions. The authors demonstrate that upon conditions of amino acid starvation, TIA-1 and TIAR assemble onto conserved 5’ terminal oligo-pyrimidine (5’TOP) elements found immediately after the 5’ cap of mRNAs encoding protein biosynthesis factors. TIA-1 and TIAR sequester the 5’TOP mRNAs in cytoplasmic stress granules, and thereby repress translation initiation until growth conditions improve. This regulation requires the mTOR and GCN2 growth signaling pathways, and occurs specifically on mRNAs containing TIA-1/TIAR binding sites immediately after the 5’ cap. This places the TIA-1 and TIAR RNA binding proteins central to cellular growth control, and describes a fundamental mechanism by which a large network of mRNAs can be co-regulated at the translational level in response to changes in the cellular environment.

Receptors in DNA Double Strand Break Repair

Michal Malewicz, Banafsheh Kadkhodaei, Nigel Kee, Nikolaos Volakakis, Ulf Hellman, Kristina Viktorsson, Chuen Yan Leung, Benjamin Chen, Rolf Lewensohn, Dik C. van Gent, David J. Chen, and Thomas Perlmann

 

Nuclear receptors are well known as ligand-regulated transcription factors. In this paper, Malewicz et al. reveal an unexpected link between nuclear receptors and DNArepair: they show that NR4A proteins, a family of orphan nuclear receptors,promote DNA double strand break repair by a mechanism that does not involvetheir normal gene regulatory function. Malewicz et al demonstrated that in response to DNA damage, NR4A proteins translocate to sites of double-strandbreak (DSB) repair, and that this process requires the activity of poly(ADP-ribose) polymerase-1 (PARP1). At DSBs, NR4As are phosphorylated by DNA-dependent protein kinase (DNA-PK), a well-studied component of the DNA repair machinery of which relevant substrates have remained elusive. Thus, these findings define NR4As as novel components of DNA damage response and functionally relevant substrates of DNA-PK in the process of double strand break repair.

 

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