Fabian Morales Polanco
Postdoctoral Scholar, Biology
Honors & Awards
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Beatriu de Pinós Fellow, The government of Catalonia, Spain (September 2024)
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MIT Catalyst Postdoctoral Fellow, Massachusetts Institute of Technology (2024)
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Intersections Science Fellow (ISFS), Yale University (2023)
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MERIT Emerging Leader, Memorial Sloan Kettering Cancer Center (2023)
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Rising Star Scholar in Molecular Genetics and Cell Biology, The University of Chicago (2023)
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Pew Postdoctoral Fellow, Postdoctoral Fellowship, The Pew Trusts (2020)
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Best Poster presentation, International Conference in Yeast Genetics and Molecular Biology (2017)
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Best Poster Presentation, Translation UK Conference, Springer (2016)
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Fondecyt (ANID) International Graduate Scholarship, Chilean Government (2014)
Professional Education
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Ingeniero, Universidad De Chile (2013)
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Licenciado, Universidad De Chile (2018)
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Doctor of Philosophy, University of Manchester (2018)
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Bachelor of Science, Universidad de Chile, Molecular Biotechnology (2013)
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Professional Title, Universidad de Chile, Molecular Biotechnology (Professional Engineer) (2014)
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Doctor of Philosophy, The University of Manchester, Biotechnology, Bioscience Enterprise and Molecular Biology (2018)
All Publications
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A developmental mechanism to regulate alternative polyadenylation in an adult stem cell lineage.
Genes & development
2024
Abstract
Alternative cleavage and polyadenylation (APA) often results in production of mRNA isoforms with either longer or shorter 3' UTRs from the same genetic locus, potentially impacting mRNA translation, localization, and stability. Developmentally regulated APA can thus make major contributions to cell type-specific gene expression programs as cells differentiate. During Drosophila spermatogenesis, ∼500 genes undergo APA when proliferating spermatogonia differentiate into spermatocytes, producing transcripts with shortened 3' UTRs, leading to profound stage-specific changes in the proteins expressed. The molecular mechanisms that specify usage of upstream polyadenylation sites in spermatocytes are thus key to understanding the changes in cell state. Here, we show that upregulation of PCF11 and Cbc, the two components of cleavage factor II (CFII), orchestrates APA during Drosophila spermatogenesis. Knockdown of PCF11 or cbc in spermatocytes caused dysregulation of APA, with many transcripts normally cleaved at a proximal site in spermatocytes now cleaved at their distal site, as in spermatogonia. Forced overexpression of CFII components in spermatogonia switched cleavage of some transcripts to the proximal site normally used in spermatocytes. Our findings reveal a developmental mechanism where changes in expression of specific cleavage factors can direct cell type-specific APA at selected genes.
View details for DOI 10.1101/gad.351649.124
View details for PubMedID 39111825
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Developmental Regulation of Alternative Polyadenylation in an Adult Stem Cell Lineage.
bioRxiv : the preprint server for biology
2024
Abstract
Co-transcriptional alternate processing of nascent mRNA molecules can make major contributions to cell type specific gene expression programs as proliferating precursor cells initiate terminal differentiation. Alternative Cleavage and Polyadenylation (APA) can result in the production of mRNA isoforms from the same gene locus with either longer or shorter 3'UTRs. In Drosophila spermatogenesis, approximately 500 genes undergo APA as proliferating spermatogonia differentiate into spermatocytes, producing transcript isoforms with shortened 3'UTRs, and resulting in profound stage specific changes in the proteins expressed. The molecular mechanisms that specify usage of upstream polyadenylation sites in spermatocytes are thus key to understanding the changes in cell state. Here, we show that PCF11 and Cbc, the two components of Cleavage factor II (CFII), orchestrate APA switching during Drosophila spermatogenesis. Knockdown of PCF11 or cbc in spermatocytes caused dysregulation of APA, with many transcripts normally cleaved at a proximal site in spermatocytes now cleaved at their distal site, as in spermatogonia. Although PCF11 is widely expressed, cbc is strongly upregulated in spermatocytes. Our findings reveal a developmental mechanism where changes in activity of specific cleavage factors can direct cell type specific APA at selected genes, presenting CFII as a key developmental regulator of APA during spermatogenesis.
View details for DOI 10.1101/2024.03.18.585561
View details for PubMedID 38562704
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Riboproteome remodeling during quiescence exit in Saccharomyces cerevisiae
iScience
2024; 27 (1): 108727
Abstract
The quiescent state is the prevalent mode of cellular life in most cells. Saccharomyces cerevisiae is a useful model for studying the molecular basis of the cell cycle, quiescence, and aging. Previous studies indicate that heterogeneous ribosomes show a specialized translation function to adjust the cellular proteome upon a specific stimulus. Using nano LC-MS/MS, we identified 69 of the 79 ribosomal proteins (RPs) that constitute the eukaryotic 80S ribosome during quiescence. Our study shows that the riboproteome is composed of 444 accessory proteins comprising cellular functions such as translation, protein folding, amino acid and glucose metabolism, cellular responses to oxidative stress, and protein degradation. Furthermore, the stoichiometry of both RPs and accessory proteins on ribosome particles is different depending on growth conditions and among monosome and polysome fractions. Deficiency of different RPs resulted in defects of translational capacity, suggesting that ribosome composition can result in changes in translational activity during quiescence.
View details for DOI 10.1016/j.isci.2023.108727
View details for PubMedCentralID PMC10792236
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A hierarchical assembly pathway directs the unique subunit arrangement of TRiC/CCT.
Molecular cell
2023
Abstract
How the essential eukaryotic chaperonin TRiC/CCT assembles from eight distinct subunits into a unique double-ring architecture remains undefined. We show TRiC assembly involves a hierarchical pathway that segregates subunits with distinct functional properties until holocomplex (HC) completion. A stable, likely early intermediate arises from small oligomers containing CCT2, CCT4, CCT5, and CCT7, contiguous subunits that constitute the negatively charged hemisphere of the TRiC chamber, which has weak affinity for unfolded actin. The remaining subunits CCT8, CCT1, CCT3, and CCT6, which comprise the positively charged chamber hemisphere that binds unfolded actin more strongly, join the ring individually. Unincorporated late-assembling subunits are highly labile in cells, which prevents their accumulation and premature substrate binding. Recapitulation of assembly in a recombinant system demonstrates that the subunits in each hemisphere readily form stable, noncanonical TRiC-like HCs with aberrant functional properties. Thus, regulation of TRiC assembly along a biochemical axis disfavors the formation of stable alternative chaperonin complexes.
View details for DOI 10.1016/j.molcel.2023.07.031
View details for PubMedID 37625406
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Nuclear and cytoplasmic spatial protein quality control is coordinated by nuclear-vacuolar junctions and perinuclear ESCRT.
Nature cell biology
2023
Abstract
Effective protein quality control (PQC), essential for cellular health, relies on spatial sequestration of misfolded proteins into defined inclusions. Here we reveal the coordination of nuclear and cytoplasmic spatial PQC. Cytoplasmic misfolded proteins concentrate in a cytoplasmic juxtanuclear quality control compartment, while nuclear misfolded proteins sequester into an intranuclear quality control compartment (INQ). Particle tracking reveals that INQ and the juxtanuclear quality control compartment converge to face each other across the nuclear envelope at a site proximal to the nuclear-vacuolar junction marked by perinuclear ESCRT-II/III protein Chm7. Strikingly, convergence at nuclear-vacuolar junction contacts facilitates VPS4-dependent vacuolar clearance of misfolded cytoplasmic and nuclear proteins, the latter entailing extrusion of nuclear INQ into the vacuole. Finding that nuclear-vacuolar contact sites are cellular hubs of spatial PQC to facilitate vacuolar clearance of nuclear and cytoplasmic inclusions highlights the role of cellular architecture in proteostasis maintenance.
View details for DOI 10.1038/s41556-023-01128-6
View details for PubMedID 37081164
View details for PubMedCentralID 6671943
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An ESCRT-dependent pathway of Nuclear and Cytoplasmic Spatial PQC is coordinated at Nuclear Vacuolar Junctions
Biorxiv
2022
View details for DOI 10.1101/2022.12.01.518779
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A Comprehensive Enumeration of the Human Proteostasis Network. 1. Components of Translation, Protein Folding, and Organelle-Specific Systems
Biorxiv
2022
View details for DOI 10.1101/2022.08.30.505920
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Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis
Nature
2022
View details for DOI 10.1038/s41586-021-04295-4
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Cotranslational Mechanisms of Protein Biogenesis and Complex Assembly in Eukaryotes
Annual Reviews of Biomedical Data Science
2022; 5
View details for DOI 10.1146/annurev-biodatasci-121721-095858
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Core Fermentation (CoFe) granules focus coordinated glycolytic mRNA localization and translation to fuel glucose fermentation.
iScience
2021; 24 (2): 102069
Abstract
Glycolysis is a fundamental metabolic pathway for glucose catabolism across biology, and glycolytic enzymes are among the most abundant proteins in cells. Their expression at such levels provides a particular challenge. Here we demonstrate that the glycolytic mRNAs are localized to granules in yeast and human cells. Detailed live cell and smFISH studies in yeast show that the mRNAs are actively translated in granules, and this translation appears critical for the localization. Furthermore, this arrangement is likely to facilitate the higher level organization and control of the glycolytic pathway. Indeed, the degree of fermentation required by cells is intrinsically connected to the extent of mRNA localization to granules. On this basis, we term these granules, core fermentation (CoFe) granules; they appear to represent translation factories, allowing high-level coordinated enzyme synthesis for a critical metabolic pathway.
View details for DOI 10.1016/j.isci.2021.102069
View details for PubMedID 33554071
View details for PubMedCentralID PMC7859310
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Glycolytic mRNAs localise and are translated in Core Fermentation (CoFe) granules to fuel glucose fermentation
BioRxiv
2020
View details for DOI 10.1101/741231
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Translation factor mRNA granules direct protein synthetic capacity to regions of polarized growth.
The Journal of cell biology
2019
Abstract
mRNA localization serves key functions in localized protein production, making it critical that the translation machinery itself is present at these locations. Here we show that translation factor mRNAs are localized to distinct granules within yeast cells. In contrast to many messenger RNP granules, such as processing bodies and stress granules, which contain translationally repressed mRNAs, these granules harbor translated mRNAs under active growth conditions. The granules require Pab1p for their integrity and are inherited by developing daughter cells in a She2p/She3p-dependent manner. These results point to a model where roughly half the mRNA for certain translation factors is specifically directed in granules or translation factories toward the tip of the developing daughter cell, where protein synthesis is most heavily required, which has particular implications for filamentous forms of growth. Such a feedforward mechanism would ensure adequate provision of the translation machinery where it is to be needed most over the coming growth cycle.
View details for DOI 10.1083/jcb.201704019
View details for PubMedID 30877141