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Impact of replicative stress on DNA replication timing control

Periodic Reporting for period 1 - RepliStressTiming (Impact of replicative stress on DNA replication timing control)

Reporting period: 2017-06-01 to 2019-05-31

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.
Work performed on this project spanned a 4-month period and primarily focused on strengthening the link between ATR kinase signaling and the timing of replication of different genomic elements. Results from these studies enabled us to further substantiate and validate a critical role of ATR and cellular proteins controlling its activation state in ensuring proper regulation of the replication timing programme in human cells.
Our results provide important new insights into the links between replication stress and replication timing. This opens up important avenues for further elucidation of the mechanistic basis and biological significance of ATR-controlled timing of the replication programme in health and disease by means of genome-wide sequencing and other approaches. Knowledge gained from such studies may be of considerable relevance for promising current efforts targeting replication stress and disruption of ATR signaling in cancer therapy.
Working model of the impact of replication stress on replication timing, based on our results.