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Updated: Feb 5, 2026

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ATR-Mediated Global Fork Slowing and Reversal Assist Fork Traverse and Prevent Chromosomal Breakage at DNA

Karun Mutreja1, Jana Krietsch1, Jeannine Hess2

  • 1Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

Cell Reports
|September 6, 2018
PubMed

Insights

Interstrand cross-links (ICLs) slow DNA replication forks globally, not just at the lesion site. This global slowing, mediated by RAD51 and ZRANB3, allows for DNA repair and prevents chromosomal damage.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Interstrand cross-links (ICLs) are DNA lesions induced by anticancer drugs, traditionally viewed as replication fork roadblocks.
  • The mechanisms by which replication forks handle ICLs, particularly single-fork traversal, remain incompletely understood.

Purpose of the Study:

  • To investigate the global impact of ICLs on DNA replication fork dynamics in human cells.
  • To elucidate the molecular mechanisms underlying replication fork adaptation to ICLs and their role in preventing genomic instability.

Main Methods:

  • Immunolabeling of ICLs combined with single-molecule assays in human cells.
  • Analysis of replication fork speed, architecture, and protein recruitment (RAD51, ZRANB3).
  • Visualization of single-fork ICL traversal using electron microscopy and assessment of ATR pathway activation.

Main Results:

  • ICL induction causes global replication fork slowing, affecting forks not directly encountering lesions.
  • RAD51 recruitment and RAD51/ZRANB3-mediated fork reversal are critical for this global slowing.
  • ATR activation is required for modulating fork speed and architecture, facilitating single-fork ICL traverse and preventing premature DNA breakage.

Conclusions:

  • Global replication fork slowing and remodeling, triggered by ICLs, provide a pro-survival mechanism.
  • This process allows more time for DNA repair and promotes bypass of residual ICLs, thereby limiting potentially damaging fork-associated processing and preserving genome integrity.
Keywords:
ATR checkpointDNA interstrand crosslinksDNA replicationDNA replication stress responseICL immunolabelingelectron microscopyfork traverseglobal fork slowingreplication fork reversal

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