Journal
MOLECULAR CELL
Volume 77, Issue 3, Pages 528-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2019.10.026
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Funding
- Swiss National Science Foundation [31003A_169959, 31003A_166451, 310030_184716]
- Czech Science Foundation [17-02080S]
- Novartis Foundation for Medical-biological Research [17C188]
- Swiss Cancer League [KFS-3802-02-2016]
- Promedica Foundation [GHDE AUGK-DZZ 1226/M]
- European Research Council (ERC) [617102]
- Neuron Fund for Support of Science
- European Regional Development Fund/OP RDE [CZ.02.1.01/0.0/0.0/16_013/0001775]
- Swiss National Science Foundation (SNF) [31003A_169959, 31003A_166451, 310030_184716] Funding Source: Swiss National Science Foundation (SNF)
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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 delta, 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.
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