Determination of the specificity of small molecule splicing modifiers acting on A-1 bulged 5’-splice sites and rational development of novel splicing modifiers.

27 Mar 2024
Job Information

Organisation/Company

INSERM U1212-CNRS UMR 5320

Research Field

Chemistry » Biochemistry
Biological sciences » Biological engineering
Computer science » Informatics

Researcher Profile

Recognised Researcher (R2)
Leading Researcher (R4)
First Stage Researcher (R1)
Established Researcher (R3)

Country

France

Application Deadline

27 Jun 2024 - 22:00 (UTC)

Type of Contract

Temporary

Job Status

Full-time

Offer Starting Date

2 Sep 2024

Is the job funded through the EU Research Framework Programme?

Not funded by an EU programme

Is the Job related to staff position within a Research Infrastructure?

No

Offer Description

Specific mRNA splicing correction using small molecules is an emerging field of drug discovery which has already provided innovative therapeutic applications in the context of inherited diseases. In the context of Spinal Muscular Atrophy and Hungtington’s disease, the small molecule acts as a molecular glue between the first particle of the spliceosome and an A-1 bulged 5’-splice site to promote specific splicing correction and provide orally available treatments. Even if the mechanism of action of the first small molecule splicing modifiers was elucidated (Campagne S. et al., Nat. Chem. Biol. 2019; Malard F. et al., Nucleic Acids Research 2024) and the concept of 5’-splice site bulge repair was discovered, there are still some open questions to fully understand the gene selectivity of splicing modifiers targeting an A-1 bulged 5’-splice site. Notably, in order to be sensitive to the small molecule, the exon has to contain an adenine in position -1 (as pointed by the 5’-splice site bulge repair mechanism) but has to contain as well a purine rich cis-RNA element in the exon, well known to recruit trans-splicing factors. In order to better understand the specificity of the A-1 splicing modifiers, the PhD student will develop a protocol to reassemble the splicing correction complex (A-1 splicing modifier, U1 snRNP, trans-splicing factors and a synthetic pre-mRNA fragment) on an in vitro transcribed mRNA fragment in commercial HeLa nuclear extract. The candidate will optimize the purification of the splicing correction complex in order to determine its composition using mass spectroscopy and its cryoEM structure. Altogether, we aim to shed the light on the quaternary structure stabilized by the A-1 splicing modifier in order to fully uncover the gene selectivity of the synthetic splicing switch but also unprecedented insights into mRNA splicing regulation. In parallel, the PhD candidate will also participate to the group project aiming at diversifying the pool of small molecule splicing modifiers and will discover using state-of-art AI-powered methods novel splicing modifiers acting on U-1 and C-1 bulged 5’-splice sites. Since many diseases originate from mutations falling at the position -1 of the 5’-splice sites, the overall aim of the project is to further explore the fundamental basis of the small molecule splicing modifier gene specificity but also to rationally design new tools for biomedicine. This PhD project is funded by the FRM (Fédération de la Recherche Médicale) in the context of the Amorcage program and the expected starting date is the 1st of September 2024.

Funding category: Financement public/privé
Fondation de la recherche médicale
PHD title: Doctorat de biologie
PHD Country: France

Requirements
Specific Requirements

We are seeking for an excellent student (having a Master or an high school engeneer diploma) who is willing to work at the interface between chemistry, biochemistry, drug discovery and structural biology in a young and dynamic group of research. Excellent skills in molecular biology, biochemistry and structural biology are expected. Previous experience in structure determination by cryoEM and a solid training in bioinformatics will be a nice add-on.

Additional Information
Work Location(s)

Number of offers available

1

Company/Institute

INSERM U1212-CNRS UMR 5320

Country

France

City

Bordeaux

Geofield

Where to apply

Website

https://www.abg.asso.fr/fr/candidatOffres/show/id_offre/121832

Contact

Website

http://www.rna-smart.com/

STATUS: EXPIRED