Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Nat Struct Mol Biol
2023 Jan 01;301:115-124. doi: 10.1038/s41594-022-00871-y.
Show Gene links
Show Anatomy links
Replication fork uncoupling causes nascent strand degradation and fork reversal.
Kavlashvili T, Liu W, Mohamed TM, Cortez D, Dewar JM.
???displayArticle.abstract???
Genotoxins cause nascent strand degradation (NSD) and fork reversal during DNA replication. NSD and fork reversal are crucial for genome stability and are exploited by chemotherapeutic approaches. However, it is unclear how NSD and fork reversal are triggered. Additionally, the fate of the replicative helicase during these processes is unknown. We developed a biochemical approach to study synchronous, localized NSD and fork reversal using Xenopus egg extracts and validated this approach with experiments in human cells. We show that replication fork uncoupling stimulates NSD of both nascent strands and progressive conversion of uncoupled forks to reversed forks. Notably, the replicative helicase remains bound during NSD and fork reversal. Unexpectedly, NSD occurs before and after fork reversal, indicating that multiple degradation steps take place. Overall, our data show that uncoupling causes NSD and fork reversal and elucidate key events that precede fork reversal.
Ait Saada,
Preserving replication fork integrity and competence via the homologous recombination pathway.
2018, Pubmed
Ait Saada,
Preserving replication fork integrity and competence via the homologous recombination pathway.
2018,
Pubmed Amunugama,
Replication Fork Reversal during DNA Interstrand Crosslink Repair Requires CMG Unloading.
2018,
Pubmed
,
Xenbase Bai,
HLTF Promotes Fork Reversal, Limiting Replication Stress Resistance and Preventing Multiple Mechanisms of Unrestrained DNA Synthesis.
2020,
Pubmed Berti,
Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition.
2013,
Pubmed Berti,
The plasticity of DNA replication forks in response to clinically relevant genotoxic stress.
2020,
Pubmed Bétous,
SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication.
2012,
Pubmed Biebricher,
PICH: a DNA translocase specially adapted for processing anaphase bridge DNA.
2013,
Pubmed Byun,
Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint.
2005,
Pubmed
,
Xenbase Chaudhury,
FANCD2-controlled chromatin access of the Fanconi-associated nuclease FAN1 is crucial for the recovery of stalled replication forks.
2014,
Pubmed Cong,
Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.
2021,
Pubmed Coquel,
SAMHD1 acts at stalled replication forks to prevent interferon induction.
2018,
Pubmed Couch,
ATR phosphorylates SMARCAL1 to prevent replication fork collapse.
2013,
Pubmed
,
Xenbase Deegan,
CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold.
2020,
Pubmed Deng,
Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements.
2019,
Pubmed
,
Xenbase Dewar,
The mechanism of DNA replication termination in vertebrates.
2015,
Pubmed
,
Xenbase Dewar,
CRL2Lrr1 promotes unloading of the vertebrate replisome from chromatin during replication termination.
2017,
Pubmed
,
Xenbase Dias,
Understanding and overcoming resistance to PARP inhibitors in cancer therapy.
2021,
Pubmed Dungrawala,
RADX Promotes Genome Stability and Modulates Chemosensitivity by Regulating RAD51 at Replication Forks.
2017,
Pubmed Dupré,
A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex.
2008,
Pubmed
,
Xenbase Fugger,
FBH1 Catalyzes Regression of Stalled Replication Forks.
2015,
Pubmed Graham,
Independent and Stochastic Action of DNA Polymerases in the Replisome.
2017,
Pubmed Hanada,
The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks.
2007,
Pubmed Hashimoto,
Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis.
2010,
Pubmed
,
Xenbase Heintzman,
Topoisomerase II Is Crucial for Fork Convergence during Vertebrate Replication Termination.
2019,
Pubmed
,
Xenbase Higgs,
BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks.
2015,
Pubmed Hu,
The intra-S phase checkpoint targets Dna2 to prevent stalled replication forks from reversing.
2012,
Pubmed Huang,
The DNA translocase FANCM/MHF promotes replication traverse of DNA interstrand crosslinks.
2013,
Pubmed Hunter,
The single-end invasion: an asymmetric intermediate at the double-strand break to double-holliday junction transition of meiotic recombination.
2001,
Pubmed Iannascoli,
The WRN exonuclease domain protects nascent strands from pathological MRE11/EXO1-dependent degradation.
2015,
Pubmed Klein Douwel,
XPF-ERCC1 acts in Unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4.
2014,
Pubmed
,
Xenbase Kolinjivadi,
Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of Brca2 and Stable Rad51 Nucleofilaments.
2017,
Pubmed
,
Xenbase Kose,
Duplex DNA engagement and RPA oppositely regulate the DNA-unwinding rate of CMG helicase.
2020,
Pubmed Lebofsky,
DNA replication in nucleus-free Xenopus egg extracts.
2009,
Pubmed
,
Xenbase Lemaçon,
MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells.
2017,
Pubmed Liu,
A Selective Small Molecule DNA2 Inhibitor for Sensitization of Human Cancer Cells to Chemotherapy.
2016,
Pubmed Liu,
Two replication fork remodeling pathways generate nuclease substrates for distinct fork protection factors.
2020,
Pubmed Long,
Regression supports two mechanisms of fork processing in phage T4.
2008,
Pubmed Low,
The DNA replication fork suppresses CMG unloading from chromatin before termination.
2020,
Pubmed
,
Xenbase Manosas,
Direct observation of stalled fork restart via fork regression in the T4 replication system.
2012,
Pubmed Mason,
Non-enzymatic roles of human RAD51 at stalled replication forks.
2019,
Pubmed Masuda-Ozawa,
Single-molecule sorting reveals how ubiquitylation affects substrate recognition and activities of FBH1 helicase.
2013,
Pubmed Mijic,
Replication fork reversal triggers fork degradation in BRCA2-defective cells.
2017,
Pubmed Mutreja,
ATR-Mediated Global Fork Slowing and Reversal Assist Fork Traverse and Prevent Chromosomal Breakage at DNA Interstrand Cross-Links.
2018,
Pubmed Nieminuszczy,
EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2.
2019,
Pubmed Paudyal,
Dna2 initiates resection at clean DNA double-strand breaks.
2017,
Pubmed
,
Xenbase Petermann,
Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair.
2010,
Pubmed Quinet,
Replication Fork Reversal: Players and Guardians.
2017,
Pubmed Quinet,
PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells.
2020,
Pubmed Ray Chaudhuri,
Replication fork stability confers chemoresistance in BRCA-deficient cells.
2016,
Pubmed Ray Chaudhuri,
Topoisomerase I poisoning results in PARP-mediated replication fork reversal.
2012,
Pubmed
,
Xenbase Rickman,
Advances in understanding DNA processing and protection at stalled replication forks.
2019,
Pubmed Rickman,
Distinct roles of BRCA2 in replication fork protection in response to hydroxyurea and DNA interstrand cross-links.
2020,
Pubmed Schlacher,
Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11.
2011,
Pubmed Somyajit,
Homology-directed repair protects the replicating genome from metabolic assaults.
2021,
Pubmed Sparks,
The CMG Helicase Bypasses DNA-Protein Cross-Links to Facilitate Their Repair.
2019,
Pubmed
,
Xenbase Taglialatela,
Restoration of Replication Fork Stability in BRCA1- and BRCA2-Deficient Cells by Inactivation of SNF2-Family Fork Remodelers.
2017,
Pubmed Thangavel,
DNA2 drives processing and restart of reversed replication forks in human cells.
2015,
Pubmed Tian,
The ZATT-TOP2A-PICH Axis Drives Extensive Replication Fork Reversal to Promote Genome Stability.
2021,
Pubmed Timson,
Hydroxyurea.
1975,
Pubmed Tirman,
Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells.
2021,
Pubmed Toledo,
ATR prohibits replication catastrophe by preventing global exhaustion of RPA.
2013,
Pubmed Vallerga,
Rad51 recombinase prevents Mre11 nuclease-dependent degradation and excessive PrimPol-mediated elongation of nascent DNA after UV irradiation.
2015,
Pubmed Vrtis,
Single-strand DNA breaks cause replisome disassembly.
2021,
Pubmed
,
Xenbase Vujanovic,
Replication Fork Slowing and Reversal upon DNA Damage Require PCNA Polyubiquitination and ZRANB3 DNA Translocase Activity.
2017,
Pubmed Walter,
Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase alpha.
2000,
Pubmed
,
Xenbase Walter,
Regulated chromosomal DNA replication in the absence of a nucleus.
1998,
Pubmed
,
Xenbase Wasserman,
Replication Fork Activation Is Enabled by a Single-Stranded DNA Gate in CMG Helicase.
2019,
Pubmed Wong,
Processing of DNA Polymerase-Blocking Lesions during Genome Replication Is Spatially and Temporally Segregated from Replication Forks.
2020,
Pubmed Zellweger,
Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells.
2015,
Pubmed Zhang,
DNA interstrand cross-link repair requires replication-fork convergence.
2015,
Pubmed
,
Xenbase Zhu,
Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends.
2008,
Pubmed
