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UPF1 relationship to FMR1 mRNA stability

Grant number: 23/15119-5
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): December 01, 2023
Effective date (End): November 30, 2024
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Luciana Amaral Haddad
Grantee:Luara Beatriz Gheler de Novaes
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


The FMR1 gene encodes an RNA-binding protein named FMRP, whose function is associated with translational control in neurons. Expansions of cytosine-guanine-guanine (CGG) repeats in the 5' UTR region of FMR1 are related to clinical conditions such as fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency. Literature data indicate that FMRP is capable of directly interacting with UPF1, a key factor involved in nonsense-mediated RNA decay (NMD), leading to the stabilization of messenger RNAs targeted to NMD. In our laboratory, it was observed that the quantity of RT-PCR amplicons with FMR1 exonic junctions 10-11, 13-15B and 13-15C was unaffected by knocking-down UPF1 in HEK293T cells, while amplicons with exonic junctions 13-14 and 14-15A had a reduction in their quantity. Altogether, the evidence indicates that besides escaping NMD certain FMR1 mRNA may be stabilized by UPF1 protein independently on NMD. Therefore, our working hypothesis is that there is at least one binding site for UPF1 in the FMR1 mRNA and it is located between splice acceptor sites 15A and 15B. To test this hypothesis, we will use HBB minigenes in fusion with FMR1 exon 15 as an experimental model. Furthermore, we will perform quantitative RT-PCR to analyze the amount of transgene mRNA.

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