TY - JOUR T1 - Function of FMRP Domains in Regulating Distinct Roles of Neuronal Protein Synthesis. JF - Mol Neurobiol Y1 - 2022 A1 - D'Souza, Michelle Ninochka A1 - Ramakrishna, Sarayu A1 - Radhakrishna, Bindushree K A1 - Jhaveri, Vishwaja A1 - Ravindran, Sreenath A1 - Yeramala, Lahari A1 - Nair, Deepak A1 - Palakodeti, Dasaradhi A1 - Muddashetty, Ravi S KW - Fragile X Mental Retardation Protein KW - Fragile X Syndrome KW - Humans KW - Microtubules KW - Neurons KW - Protein Biosynthesis KW - Ribosomes KW - RNA, Messenger AB -

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.

VL - 59 IS - 12 ER - TY - JOUR T1 - FMRP Interacts with C/D Box snoRNA in the Nucleus and Regulates Ribosomal RNA Methylation. JF - iScience Y1 - 2018 A1 - D'Souza, Michelle Ninochka A1 - Gowda, Naveen Kumar Chandappa A1 - Tiwari, Vishal A1 - Babu, Rosana Ottakandathil A1 - Anand, Praveen A1 - Dastidar, Sudhriti Ghosh A1 - Singh, Randhir A1 - James, Owen G A1 - Selvaraj, Bhuvaneish A1 - Pal, Rakhi A1 - Ramesh, Arati A1 - Chattarji, Sumantra A1 - Chandran, Siddharthan A1 - Gulyani, Akash A1 - Palakodeti, Dasaradhi A1 - Muddashetty, Ravi S AB -

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.

VL - 9 ER -