Transcription-Replication Conflict Orientation Modulates R-Loop Levels and Activates Distinct DNA Damage Responses

Conflicts between transcription and replication are a potent source of DNA damage. Co-transcriptional R-loops could aggravate such conflicts by creating an additional barrier to replication fork progression. Here, we use a defined episomal system to investigate how conflict orientation and R-loop fo...

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Bibliographic Details
Published in:Cell Vol. 170; no. 4; p. 774
Main Authors: Hamperl, Stephan, Bocek, Michael J, Saldivar, Joshua C, Swigut, Tomek, Cimprich, Karlene A
Format: Journal Article
Language:English
Published: United States 10.08.2017
Subjects:
DNA Damage
DNA Replication
DNA Replication Timing
Genomic Instability
HEK293 Cells
Humans
Plasmids
Transcription, Genetic
DNA-damage response
DNA replication
replication stress
transcription-replication conflicts
R-loops
genome instability
ISSN:1097-4172, 1097-4172
Online Access:Get more information
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Summary:Conflicts between transcription and replication are a potent source of DNA damage. Co-transcriptional R-loops could aggravate such conflicts by creating an additional barrier to replication fork progression. Here, we use a defined episomal system to investigate how conflict orientation and R-loop formation influence genome stability in human cells. R-loops, but not normal transcription complexes, induce DNA breaks and orientation-specific DNA damage responses during conflicts with replication forks. Unexpectedly, the replisome acts as an orientation-dependent regulator of R-loop levels, reducing R-loops in the co-directional (CD) orientation but promoting their formation in the head-on (HO) orientation. Replication stress and deregulated origin firing increase the number of HO collisions leading to genome-destabilizing R-loops. Our findings connect DNA replication to R-loop homeostasis and suggest a mechanistic basis for genome instability resulting from deregulated DNA replication, observed in cancer and other disease states.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2017.07.043