Fork Cleavage-Religation Cycle and Active Transcription Mediate Replication Restart after Fork Stalling at Co-transcriptional R-Loops

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 R...

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Vydané v:	Molecular cell Ročník 77; číslo 3; s. 528
Hlavní autori:	Chappidi, Nagaraja, Nascakova, Zuzana, Boleslavska, Barbora, Zellweger, Ralph, Isik, Esin, Andrs, Martin, Menon, Shruti, Dobrovolna, Jana, Balbo Pogliano, Chiara, Matos, Joao, Porro, Antonio, Lopes, Massimo, Janscak, Pavel
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 06.02.2020
Predmet:	Cell Line, Tumor DNA Ligases - metabolism DNA Polymerase III - metabolism DNA Replication - genetics DNA Replication - physiology DNA-Binding Proteins - metabolism Endodeoxyribonucleases - metabolism Endonucleases - genetics Endonucleases - metabolism HeLa Cells Humans R-Loop Structures - genetics R-Loop Structures - physiology Rad51 Recombinase - genetics Rad51 Recombinase - metabolism Rad51 Recombinase - physiology Rad52 DNA Repair and Recombination Protein - metabolism RecQ Helicases - metabolism RecQ Helicases - physiology Transcription, Genetic - genetics MUS81 replication stress transcription-replication conflict R-loop replication restart RECQ5 DNA ligase IV replication fork reversal
ISSN:	1097-4164, 1097-4164
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Abstract	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.
AbstractList	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. 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.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.
Author	Boleslavska, Barbora Matos, Joao Balbo Pogliano, Chiara Menon, Shruti Zellweger, Ralph Andrs, Martin Isik, Esin Janscak, Pavel Dobrovolna, Jana Chappidi, Nagaraja Lopes, Massimo Nascakova, Zuzana Porro, Antonio
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SubjectTerms	Cell Line, Tumor DNA Ligases - metabolism DNA Polymerase III - metabolism DNA Replication - genetics DNA Replication - physiology DNA-Binding Proteins - metabolism Endodeoxyribonucleases - metabolism Endonucleases - genetics Endonucleases - metabolism HeLa Cells Humans R-Loop Structures - genetics R-Loop Structures - physiology Rad51 Recombinase - genetics Rad51 Recombinase - metabolism Rad51 Recombinase - physiology Rad52 DNA Repair and Recombination Protein - metabolism RecQ Helicases - metabolism RecQ Helicases - physiology Transcription, Genetic - genetics
Title	Fork Cleavage-Religation Cycle and Active Transcription Mediate Replication Restart after Fork Stalling at Co-transcriptional R-Loops
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