%0 Journal Article %J Mol Neurobiol %D 2022 %T Function of FMRP Domains in Regulating Distinct Roles of Neuronal Protein Synthesis. %A D'Souza, Michelle Ninochka %A Ramakrishna, Sarayu %A Radhakrishna, Bindushree K %A Jhaveri, Vishwaja %A Ravindran, Sreenath %A Yeramala, Lahari %A Nair, Deepak %A Palakodeti, Dasaradhi %A Muddashetty, Ravi S %K Fragile X Mental Retardation Protein %K Fragile X Syndrome %K Humans %K Microtubules %K Neurons %K Protein Biosynthesis %K Ribosomes %K RNA, Messenger %X

The Fragile-X Mental Retardation Protein (FMRP) is an RNA binding protein that regulates translation of mRNAs essential for synaptic development and plasticity. FMRP interacts with a specific set of mRNAs, aids in their microtubule-dependent transport and regulates their translation through its association with ribosomes. However, the biochemical role of FMRP's domains in forming neuronal granules and associating with microtubules and ribosomes is currently undefined. We report that the C-terminus domain of FMRP is sufficient to bind to ribosomes akin to the full-length protein. Furthermore, the C-terminus domain alone is essential and responsible for FMRP-mediated neuronal translation repression. However, dendritic distribution of FMRP and its microtubule association is favored by the synergistic combination of FMRP domains rather than individual domains. Interestingly, we show that the phosphorylation of hFMRP at Serine-500 is important in modulating the dynamics of translation by controlling ribosome association. This is a fundamental mechanism governing the size and number of FMRP puncta that contain actively translating ribosomes. Finally through the use of pathogenic mutations, we emphasize the hierarchical contribution of FMRP's domains in translation regulation.

%B Mol Neurobiol %V 59 %P 7370-7392 %8 2022 Dec %G eng %N 12 %R 10.1007/s12035-022-03049-1 %0 Journal Article %J iScience %D 2018 %T FMRP Interacts with C/D Box snoRNA in the Nucleus and Regulates Ribosomal RNA Methylation. %A D'Souza, Michelle Ninochka %A Gowda, Naveen Kumar Chandappa %A Tiwari, Vishal %A Babu, Rosana Ottakandathil %A Anand, Praveen %A Dastidar, Sudhriti Ghosh %A Singh, Randhir %A James, Owen G %A Selvaraj, Bhuvaneish %A Pal, Rakhi %A Ramesh, Arati %A Chattarji, Sumantra %A Chandran, Siddharthan %A Gulyani, Akash %A Palakodeti, Dasaradhi %A Muddashetty, Ravi S %X

FMRP is an RNA-binding protein that is known to localize in the cytoplasm and in the nucleus. Here, we have identified an interaction of FMRP with a specific set of C/D box snoRNAs in the nucleus. C/D box snoRNAs guide 2'O methylations of ribosomal RNA (rRNA) on defined sites, and this modification regulates rRNA folding and assembly of ribosomes. 2'O methylation of rRNA is partial on several sites in human embryonic stem cells, which results in ribosomes with differential methylation patterns. FMRP-snoRNA interaction affects rRNA methylation on several of these sites, and in the absence of FMRP, differential methylation pattern of rRNA is significantly altered. We found that FMRP recognizes ribosomes carrying specific methylation patterns on rRNA and the recognition of methylation pattern by FMRP may potentially determine the translation status of its target mRNAs. Thus, FMRP integrates its function in the nucleus and in the cytoplasm.

%B iScience %V 9 %P 399-411 %8 2018 Nov 30 %G eng %R 10.1016/j.isci.2018.11.007