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

Interstrand cross-links (ICLs) are toxic DNA lesions interfering with DNA metabolism that are induced by widely used anticancer drugs. They have long been considered absolute roadblocks for replication forks, implicating complex DNA repair processes at stalled or converging replication forks. Recent...

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Bibliographic Details
Published in:Cell reports (Cambridge) Vol. 24; no. 10; pp. 2629 - 2642.e5
Main Authors: Mutreja, Karun, Krietsch, Jana, Hess, Jeannine, Ursich, Sebastian, Berti, Matteo, Roessler, Fabienne K., Zellweger, Ralph, Patra, Malay, Gasser, Gilles, Lopes, Massimo
Format: Journal Article
Language:English
Published: United States Elsevier Inc 04.09.2018
Cell Press
Elsevier
Subjects:
ATR checkpoint
Chemical Sciences
DNA interstrand crosslinks
DNA replication
DNA replication stress response
electron microscopy
fork traverse
global fork slowing
ICL immunolabeling
Medicinal Chemistry
replication fork reversal
DNA replication stress response
DNA replication
fork traverse
electron microscopy
ATR checkpoint
replication fork reversal
global fork slowing
DNA interstrand crosslinks
ICL immunolabeling
ISSN:2211-1247, 2211-1247
Online Access:Get full text
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Summary:Interstrand cross-links (ICLs) are toxic DNA lesions interfering with DNA metabolism that are induced by widely used anticancer drugs. They have long been considered absolute roadblocks for replication forks, implicating complex DNA repair processes at stalled or converging replication forks. Recent evidence challenged this view, proposing that single forks traverse ICLs by yet elusive mechanisms. Combining ICL immunolabeling and single-molecule approaches in human cells, we now show that ICL induction leads to global replication fork slowing, involving forks not directly challenged by ICLs. Active fork slowing is linked to rapid recruitment of RAD51 to replicating chromatin and to RAD51/ZRANB3-mediated fork reversal. This global modulation of fork speed and architecture requires ATR activation, promotes single-fork ICL traverse—here, directly visualized by electron microscopy—and prevents chromosomal breakage by untimely ICL processing. We propose that global fork slowing by remodeling provides more time for template repair and promotes bypass of residual lesions, limiting fork-associated processing. [Display omitted] •Fork slowing and reversal are also observed at forks not directly challenged by ICLs•Fork reversal assists ICL traverse and limits DSBs associated with ICL unhooking•ICL traverse can be directly visualized in human cells by electron microscopy•ATR mediates global fork slowing and reversal upon different genotoxic treatments Replication-coupled repair of DNA interstrand cross-links (ICLs) promotes resistance to chemotherapeutic treatments. Visualizing individual lesions and replication intermediates, Mutreja et al. report that forks slow down and reverse both at ICLs and away from lesions. This ATR-mediated response assists lesion bypass during replication and limits chromosomal breakage by fork-associated processing.
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Lead Contact
Present address: Chimie ParisTech, PSL University, Laboratory for Inorganic Chemical Biology, F-75005 Paris, France
Present address: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2018.08.019