RepliStressTiming · Impact of replicative stress on DNA replication timing control
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-06-01 → 2019-05-31
- EU contribution
- €200,195
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Impact of replicative stress on DNA replication timing control
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. However, 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. Based on promising preliminary observations, we hypothesize that replication stress caused by disruption of ATR signaling perturbs the carefully regulated timing by which genes are replicated. This may directly alter gene expression patterns, potentially leading to oncogene activation and/or silencing of tumor suppressors. By carefully investigating such responses and their underlying molecular mechanisms, this study will identify genes with altered transcriptional activity as a result of perturbations in replication timing and provide new insight into how ATR signaling controls replication timing to safeguard against tumorigenesis. The outcomes can better inform exploitation of replication stress in cancer therapeutics using inhibitors of ATR and related factors as a promising strategy.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark
Links
Data: CORDIS, © European Union