Transcription-replication conflict orientation modulates R-Loop levels and activates distinct DNA damage responses

• Autores: Stephan Hamperl, Michael J. Bocek, Joshua C. Saldivar, Tomek Swigut, Karlene A. Cimprich
• Localización: Cell, ISSN 0092-8674, Vol. 170, Nº. 4, 2017, págs. 774-786
• Idioma: inglés
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• Resumen

  • 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.