ATR-mediated global fork slowing and reversal assist fork traverse and prevent chromosomal breakage at DNA interstrand cross-links
Authors list
Karun Mutreja Jana Krietsch Jeannine Hess Sebastian Ursich Matteo Berti Fabienne K Roessler Ralph Zellweger Malay Patra Gilles Gasser Massimo LopesAbstract
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.
Journal details
Journal
Cell Reports
Volume
24
Issue number
10
Pages
2629-2642.e5
Available online
Publication date
Full text links
Publisher website (DOI)
10.1016/j.celrep.2018.08.019
Europe PubMed Central
30184498
Pubmed
30184498
Keywords
Type of publication
