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bioRxiv · 10.1101/155978

DNA Replication Modulates R-loop Levels to Maintain Genome Stability

Hamperl, S.·Saldivar, J. C.·Bocek, M. J.·Cimprich, K. A.
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Abstract

Conflicts between transcription and replication are a potent source of DNA damage. The transcription machinery has the potential to aggravate such conflicts by generating co-transcriptional R-loops as an additional barrier to replication fork progression. Here, we investigate the influence of conflict orientation and R-loop formation on genome stability in human cells using a defined episomal system. This approach reveals that head-on (HO) and co-directional (CD) conflicts induce distinct DNA damage responses. Unexpectedly, the replisome acts as an orientation-dependent regulator of R-loop levels, reducing R-loops in the CD orientation but promoting their formation in the HO orientation. Replication stress and deregulated origin firing increase the number of HO collisions leading to genome-destabilizing R-loops. Our findings not only uncover an intrinsic function of the replisome in R-loop homeostasis, but also suggest a mechanistic basis for genome instability associated with deregulated DNA replication, which is observed in many disease states, including cancer.

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Hamperl, S., Saldivar, J. C., Bocek, M. J., Cimprich, K. A.. 2017-06-26. DNA Replication Modulates R-loop Levels to Maintain Genome Stability. https://doi.org/10.1101/155978

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