Deciphering molecular mechanisms that resolve mutagenic DNA G-quadruplex structures

Información del proyecto

ReXeG

Identificador del acuerdo de subvención: 750035

DOI

10.3030/750035

Proyecto finalizado el 15 Diciembre 2018

Fecha de la firma de la CE 23 Febrero 2017

Fecha de inicio 1 Marzo 2017

Fecha de finalización 28 Febrero 2019

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 165 598,80

Aportación de la UE

€ 165 598,80

Coordinado por

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Netherlands

Objetivo

G-quadruplex (G4) structures are stable four-stranded nucleic acids assemblies that can form in guanine-rich DNA. Their recent visualization in mammalian cells has established G4 structure formation throughout the genome and fueled research into understanding the biological implications of these structures in cell regulation.
G4 sequence motifs are abundant and conserved in our genome. G4 structures form transiently and regulate numerous cellular processes such as DNA replication, transcription and telomere maintenance. Importantly, these structures also come at a cost as they are able to induce genomic instability in certain cellular conditions, for example in cancer cells that suffer from replication stress.
Currently, the mechanisms that form and resolve G4 structures are unknown. Several helicases can unwind these stable DNA structures in vitro but it is unclear whether and how these helicases function in vivo. Understanding the biochemical mechanisms that resolve G4 structures is crucial to further understand their function and how they induce DNA mutations in the cell.
In this project, I propose to decipher the molecular mechanisms of G4 structures unwinding. The groundbreaking nature of this proposal is the use of a unique method to follow G-quadruplex unfolding in time under near-physiological conditions in vitro. This method, which was recently established in the host laboratory, uses DNA replication stalling and bypass at defined G4 structures as a direct readout for G4 stability and unwinding. This gives me the opportunity to address important aspects that have not been studied under physiological conditions before:
Aim 1: To determine the stability and unwinding properties of distinct G4 conformations.
Aim 2: To identify molecular mechanisms and novel proteins in G4 unwinding.
The results of this project will give important new insights into G4 regulation, an unexplored but important biological process.

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › ácido nucleico
• ciencias naturales › ciencias biológicas › genética › ADN
• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias naturales › ciencias químicas › química analítica › espectrometría de masas
• ciencias naturales › ciencias biológicas › genética › genoma

Palabras clave

• G-quadruplex (G4) structures
• DNA replication
• Xenopus egg extract
• genome stability
• DNA-protein interaction

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2016 - Individual Fellowships
  

Régimen de financiación

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

Convocatoria de propuestas

H2020-MSCA-IF-2016

Coordinador

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW

• Aportación neta de la UEn: € 165 598,80
• Dirección: KLOVENIERSBURGWAL 29 HET TRIPPENHUIS ; 1011 JV AMSTERDAM ; Países Bajos
• Tipo de actividad: Research Organisations
• Coste total: € 165 598,80