Fork Cleavage-Religation Cycle and Active Transcription Mediate Replication Restart after Fork Stalling at Co-transcriptional R-Loops
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
31759821
DOI
10.1016/j.molcel.2019.10.026
PII: S1097-2765(19)30804-4
Knihovny.cz E-resources
- Keywords
- DNA ligase IV, MUS81, R-loop, RECQ5, replication fork reversal, replication restart, replication stress, transcription-replication conflict,
- MeSH
- Rad52 DNA Repair and Recombination Protein metabolism MeSH
- DNA-Binding Proteins metabolism MeSH
- DNA Ligases metabolism MeSH
- DNA Polymerase III metabolism MeSH
- Endodeoxyribonucleases metabolism MeSH
- Endonucleases genetics metabolism MeSH
- Transcription, Genetic genetics MeSH
- HeLa Cells MeSH
- RecQ Helicases metabolism physiology MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- R-Loop Structures genetics physiology MeSH
- Rad51 Recombinase genetics metabolism physiology MeSH
- DNA Replication genetics physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Rad52 DNA Repair and Recombination Protein MeSH
- DNA-Binding Proteins MeSH
- DNA Ligases MeSH
- DNA Polymerase III MeSH
- Endodeoxyribonucleases MeSH
- Endonucleases MeSH
- RecQ Helicases MeSH
- Lig4 protein, Arabidopsis MeSH Browser
- MUS81 protein, human MeSH Browser
- RAD51 protein, human MeSH Browser
- RAD52 protein, human MeSH Browser
- RECQL protein, human MeSH Browser
- RECQL5 protein, human MeSH Browser
- Rad51 Recombinase MeSH
- XRCC4 protein, human MeSH Browser
Formation of co-transcriptional R-loops underlies replication fork stalling upon head-on transcription-replication encounters. Here, we demonstrate that RAD51-dependent replication fork reversal induced by R-loops is followed by the restart of semiconservative DNA replication mediated by RECQ1 and RECQ5 helicases, MUS81/EME1 endonuclease, RAD52 strand-annealing factor, the DNA ligase IV (LIG4)/XRCC4 complex, and the non-catalytic subunit of DNA polymerase δ, POLD3. RECQ5 disrupts RAD51 filaments assembled on stalled forks after RECQ1-mediated reverse branch migration, preventing a new round of fork reversal and facilitating fork cleavage by MUS81/EME1. MUS81-dependent DNA breaks accumulate in cells lacking RAD52 or LIG4 upon induction of R-loop formation, suggesting that RAD52 acts in concert with LIG4/XRCC4 to catalyze fork religation, thereby mediating replication restart. The resumption of DNA synthesis after R-loop-associated fork stalling also requires active transcription, the restoration of which depends on MUS81, RAD52, LIG4, and the transcription elongation factor ELL. These findings provide mechanistic insights into transcription-replication conflict resolution.
References provided by Crossref.org
PPM1D activity promotes the replication stress caused by cyclin E1 overexpression
Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor
Excessive reactive oxygen species induce transcription-dependent replication stress
The importance of nuclear RAGE-Mcm2 axis in diabetes or cancer-associated replication stress
RECQ5: A Mysterious Helicase at the Interface of DNA Replication and Transcription
