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Published on: May 13, 2021
The ATR pathway: fine-tuning the fork
Renee D Paulsen1, Karlene A Cimprich
1Department of Chemical and Systems Biology, Stanford University, 318 Campus Drive, Stanford, CA 94305-5441, USA.
Abstract:
The proper detection and repair of DNA damage is essential to the maintenance of genomic stability. The genome is particularly vulnerable during DNA replication, when endogenous and exogenous events can hinder replication fork progression. Stalled replication forks can fold into deleterious conformations and are also unstable structures that are prone to collapse or break. These events can lead to inappropriate processing of the DNA, ultimately resulting in genomic instability, chromosomal alterations and cancer. To cope with stalled replication forks, the cell relies on the replication checkpoint to block cell cycle progression, downregulate origin firing, stabilize the fork itself, and restart replication. The ATR (ATM and Rad3-related) kinase and its downstream effector kinase, Chk1, are central regulators of the replication checkpoint. Loss of these checkpoint proteins causes replication fork collapse and chromosomal rearrangements which may ultimately predispose affected individuals to cancer. This review summarizes our current understanding of how the ATR pathway recognizes and stabilizes stalled replication forks.
Insights
The ATR pathway is crucial for stabilizing stalled DNA replication forks, preventing genomic instability and cancer. Its proper function ensures DNA repair and cell cycle regulation.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Genomic stability is vital and threatened during DNA replication by various damaging events.
- Replication fork stalling can lead to DNA damage, genomic instability, and cancer.
- The cell utilizes a replication checkpoint to manage stalled forks.
Purpose of the Study:
- To review the mechanisms by which the ATR pathway recognizes and stabilizes stalled replication forks.
- To highlight the importance of ATR and Chk1 in the replication checkpoint.
Main Methods:
- This review synthesizes current research on the ATR pathway and replication checkpoint.
- Focuses on the molecular mechanisms of fork stabilization.
Main Results:
- The ATR-Chk1 pathway is central to the replication checkpoint, blocking cell cycle progression and stabilizing forks.
- Loss of ATR or Chk1 leads to replication fork collapse and chromosomal instability.
- ATR pathway activation is essential for preventing genomic rearrangements.
Conclusions:
- The ATR pathway plays a critical role in maintaining genomic integrity by managing stalled replication forks.
- Dysregulation of ATR signaling can predispose individuals to cancer.
- Understanding ATR's role is key to developing therapeutic strategies for replication stress-induced diseases.
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