ATR-Mediated Global Fork Slowing and Reversal Assist Fork Traverse and Prevent Chromosomal Breakage at DNA Interstrand Cross-Links
| Autor: | Mutreja, Karun, Krietsch, Jana, Hess, Jeannine, Ursich, Sebastian, Berti, Matteo, Roessler, Fabienne K, Zellweger, Ralph, Patra, Malay, Gasser, Gilles, Lopes, Massimo |
|---|---|
| Přispěvatelé: | University of Zurich, Lopes, Massimo, Laval University Medical Research Center - Cancer Research Unit, Université Laval [Québec] (ULaval), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL), ERC Grant number: 681679 / Project acronym: PhotoMedMet, Project acronym: PhotoMedMet, European Project: 681679, H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC),681679,PhotoMedMet(2017) |
| Rok vydání: | 2017 |
| Předmět: |
DNA Replication
10061 Institute of Molecular Cancer Research Blotting Western Fluorescent Antibody Technique 610 Medicine & health Chromosome Breakage [CHIM.THER]Chemical Sciences/Medicinal Chemistry DNA Flow Cytometry DNA-Binding Proteins Microscopy Electron lcsh:Biology (General) 1300 General Biochemistry Genetics and Molecular Biology Cell Line Tumor 570 Life sciences biology Humans Comet Assay Rad51 Recombinase lcsh:QH301-705.5 DNA Damage |
| Zdroj: | Cell Reports Cell Reports, Elsevier Inc, 2018, 24 (10), pp.2629-2642.e5. ⟨10.1016/j.celrep.2018.08.019⟩ Cell Reports, Vol 24, Iss 10, Pp 2629-2642.e5 (2018) |
| ISSN: | 2211-1247 |
| Popis: | 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. : 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. Keywords: DNA replication, DNA replication stress response, replication fork reversal, fork traverse, DNA interstrand crosslinks, ATR checkpoint, global fork slowing, electron microscopy, ICL immunolabeling |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|