Impact of replicative stress on DNA replication timing control

Información del proyecto

RepliStressTiming

Identificador del acuerdo de subvención: 745646

DOI

10.3030/745646

Proyecto finalizado el 14 Febrero 2018

Fecha de la firma de la CE 24 Febrero 2017

Fecha de inicio 1 Junio 2017

Fecha de finalización 31 Mayo 2019

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 200 194,80

Aportación de la UE

€ 200 194,80

Coordinado por

KOBENHAVNS UNIVERSITET
Denmark

Objetivo

Replication stress has emerged as a prominent driver of genomic instability. The ATR kinase is a master regulator of the cellular response to replication stress and defects in ATR activation or loss of its signaling components leads to DNA damage, genomic instability and tumorigenesis. Yet the direct mechanisms by which ATR signaling prevents these repercussions remain poorly understood. The primary aim of this study is to investigate a novel role for ATR in regulating the cellular replication timing program and corresponding gene expression. I hypothesize that replication stress caused by disruption of ATR signaling perturbs the carefully regulated timing by which genes are replicated. This directly alters gene expression patterns, potentially leading to oncogene activation and/or silencing of tumor suppressors. This idea is substantiated by my preliminary results indicating striking shifts in replication timing of select genomic loci under defective ATR signaling. Furthermore, a recent finding that ATR maintains the transcriptional status of genes in the vicinity of stalled forks alludes to a similar connection. This timely study will be the first to identify genes with altered transcriptional activity as a result of perturbations in replication timing under ATR-mediated replication stress. Functional characterization of these gene products will provide new insight into how ATR determines replication timing and direct mechanistic basis for how ATR signaling safeguards against tumorigenesis. The outcomes can better inform exploitation of replication stress in cancer therapeutics in the form of ATR inhibitors and underlying pathologies in ATR-deficient Seckel syndrome and associated hereditary diseases. By bridging the fields of replication stress and timing, I will gain new skills in transcriptomics, chromatin biology and in vivo tumor models to complement my previous expertise in replication timing and genomics, laying strong foundations for my independent career.

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › genética › ADN
• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias médicas y de la salud › medicina clínica › oncología
• ciencias médicas y de la salud › medicina básica › patología

Palabras clave

• Replication stress
• Replication timing
• ATR signaling
• Genome instability
• Tumorigenesis
• Cancer
• Stalled replication forks
• Gene expression regulation
• In vivo model

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

KOBENHAVNS UNIVERSITET

• Aportación neta de la UEn: € 200 194,80
• Dirección: NORREGADE 10 ; 1165 KOBENHAVN ; Dinamarca
• Región: Danmark › Hovedstaden › Byen København
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 200 194,80