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Related Concept Videos

Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart, a...
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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage Can Stall the Cell Cycle02:36

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The Spindle Assembly Checkpoint02:19

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Related Experiment Video

Updated: May 9, 2026

CD Spectroscopy to Study DNA-Protein Interactions
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CD Spectroscopy to Study DNA-Protein Interactions

Published on: February 10, 2022

ATR phosphorylates SMARCAL1 to prevent replication fork collapse.

Frank B Couch1, Carol E Bansbach, Robert Driscoll

  • 1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

Genes & Development
|July 23, 2013
PubMed
Summary

The ataxia telangiectasia and Rad3-related (ATR) kinase prevents DNA replication fork collapse by phosphorylating SMARCAL1. Inhibiting ATR leads to rapid cell death and genome instability.

Keywords:
ATRDNA damage responseDNA replicationHARPSMARCAL1cell cycle checkpoint

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Area of Science:

  • Cellular biology
  • Molecular oncology
  • DNA replication and repair

Background:

  • The DNA damage response kinase ATR is crucial for coordinating cellular responses to replication stress.
  • ATR's role in regulating DNA synthesis during replication stress is vital for cancer cell viability, positioning ATR as a therapeutic target.

Purpose of the Study:

  • To elucidate the precise mechanisms by which ATR regulates DNA synthesis under replication stress.
  • To investigate the consequences of acute ATR inhibition on DNA replication and fork stability.

Main Methods:

  • Utilized selective ATR inhibitors in mammalian and Xenopus systems.
  • Analyzed replication initiation timing, elongation rates, and DNA fork collapse.
  • Investigated the roles of SLX4, CtIP, and SMARCAL1 in fork collapse.

Main Results:

  • Acute ATR inhibition caused rapid cell lethality, disrupted replication initiation timing, slowed elongation, and induced fork collapse.
  • Fork collapse involved SLX4-dependent cleavage and CtIP-dependent resection, with SMARCAL1 contributing to aberrant fork processing.
  • ATR-mediated phosphorylation of SMARCAL1 at S652 limits its fork regression activity, preventing collapse.

Conclusions:

  • ATR signaling, through SMARCAL1 phosphorylation, is essential for preventing replication fork collapse and maintaining genome integrity.
  • Targeting ATR offers a promising strategy for cancer therapy by inducing replication stress and cell death.