FMRP Interacts with C/D Box snoRNA in the Nucleus and Regulates Ribosomal RNA Methylation

D’Souza, Michelle Ninochka; Gowda, Naveen Kumar Chandappa; Tiwari, Vishal; Babu, Rosana Ottakandathil; Dastidar, Sudhriti Ghosh; Singh, Randhir; James, Owen G; Selvaraj, Bhuvaneish T.; Pal, Rakhi; Ramesh, Arati; Chattarji, Sumantra; Chandran, Siddharthan; Gulyani, Akash; Palakodeti, Dasaradhi; Muddashetty, Ravi

doi:10.1016/j.isci.2019.01.026

Cited by 7 publications

(9 citation statements)

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“…As depicted in Fig. 1A, FMRP was expressed in many types of non-neuronal cells, consistent with findings in thrombocytes [45] and human embryonic stem cells [46]. Mouse brain lysate was used as neuronal tissue control.…”

Section: Ubiquitous Expression Of Fmrp In Human Cellssupporting

confidence: 84%

Novel FMRP interaction networks linked to cellular stress

et al. 2020

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Silencing of the fragile X mental retardation 1 (FMR1) gene and consequently lack of synthesis of FMR protein (FMRP) are associated with fragile X syndrome, which is one of the most prevalent inherited intellectual disabilities, with additional roles in increased viral infection, liver disease, and reduced cancer risk. FMRP plays critical roles in chromatin dynamics, RNA binding, mRNA transport, and mRNA translation. However, the underlying molecular mechanisms, including the (sub)cellular FMRP protein networks, remain elusive. Here, we employed affinity pull‐down and quantitative LC‐MS/MS analyses with FMRP. We identified known and novel candidate FMRP‐binding proteins as well as protein complexes. FMRP interacted with 180 proteins, 28 of which interacted with its N terminus. Interaction with the C terminus of FMRP was observed for 102 proteins, and 48 proteins interacted with both termini. This FMRP interactome comprises known FMRP‐binding proteins, including the ribosomal proteins FXR1P, NUFIP2, Caprin‐1, and numerous novel FMRP candidate interacting proteins that localize to different subcellular compartments, including CARF, LARP1, LEO1, NOG2, G3BP1, NONO, NPM1, SKIP, SND1, SQSTM1, and TRIM28. Our data considerably expand the protein and RNA interaction networks of FMRP, which thereby suggest that, in addition to its known functions, FMRP participates in transcription, RNA metabolism, ribonucleoprotein stress granule formation, translation, DNA damage response, chromatin dynamics, cell cycle regulation, ribosome biogenesis, miRNA biogenesis, and mitochondrial organization. Thus, FMRP seems associated with multiple cellular processes both under normal and cell stress conditions in neuronal as well as non‐neuronal cell types, as exemplified by its role in the formation of stress granules.

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Section: Ubiquitous Expression Of Fmrp In Human Cellssupporting

confidence: 84%

Novel FMRP interaction networks linked to cellular stress

et al. 2020

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“…As previously mentioned in the context of ESCs and ASCs, several RBFs implicated in rRNA modifications are differentially expressed between stem cells and their differentiated progenies, suggesting that rRNAs may be differentially methylated either globally or on specific sites depending on the stem cell status. Accordingly, FMRP depletion in human ESCs impacted the methylation of 24 sites while others remained unaffected [102]. Similarly, FBL knockdown in mouse ESCs impaired 2'O-Me levels of only 11 sites [153].…”

Section: Rp Tissue-specific Expression and Functionsmentioning

confidence: 94%

“…Interestingly, the drosophila FRMP represses translation by directly interacting with the 60S ribosomal subunit through RPL5 [101]. More recently, FMRP was shown to interact with several box C/D snoRNAs in human ESCs and NPCs, and to mediate differential 2'O-Me of 12 partially methylated sites of the 18S and 28S rRNAs while constitutively methylated sites remained invariable [102]. FMRP plays an essential role in stem cells by coordinating both rRNA and RP expression to control fate decisions.…”

Section: Regulation Of Rrna Modificationsmentioning

confidence: 99%

Ribosome and Translational Control in Stem Cells

Gabut

Bourdelais

Durand

2020

Cells

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Embryonic stem cells (ESCs) and adult stem cells (ASCs) possess the remarkable capacity to self-renew while remaining poised to differentiate into multiple progenies in the context of a rapidly developing embryo or in steady-state tissues, respectively. This ability is controlled by complex genetic programs, which are dynamically orchestrated at different steps of gene expression, including chromatin remodeling, mRNA transcription, processing, and stability. In addition to maintaining stem cell homeostasis, these molecular processes need to be rapidly rewired to coordinate complex physiological modifications required to redirect cell fate in response to environmental clues, such as differentiation signals or tissue injuries. Although chromatin remodeling and mRNA expression have been extensively studied in stem cells, accumulating evidence suggests that stem cell transcriptomes and proteomes are poorly correlated and that stem cell properties require finely tuned protein synthesis. In addition, many studies have shown that the biogenesis of the translation machinery, the ribosome, is decisive for sustaining ESC and ASC properties. Therefore, these observations emphasize the importance of translational control in stem cell homeostasis and fate decisions. In this review, we will provide the most recent literature describing how ribosome biogenesis and translational control regulate stem cell functions and are crucial for accommodating proteome remodeling in response to changes in stem cell fate.

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“…C/D box snoRNA (SNORDs), guide rRNA 2′-O-Methyltransferase, fibrillarin, to methylate specific bases of the rRNA ( van Nues and Watkins, 2017 ). There are over 106 SNORDs in human cells ( D'Souza et al., 2019 ). However, clues to which SNORDs decide the methylation of rRNA in conditions such as hypoxia are still to be unraveled.…”

Section: Resultsmentioning

confidence: 99%

“…The role of snoRNAs in controlling cell behavior and tumor biology is gaining attention ( Liu et al., 2020 ). Considering that each human ribosome contains around 100 ribose methylations and 100 pseudouridines and that each position is subject to individual regulation through specific snoRNA guides, the potential for heterogeneity within ribosomal subpopulations is enormous ( D'Souza et al., 2019 ; Sloan et al., 2017 ).…”

Section: Discussionmentioning

confidence: 99%