R-loop-mediated genomic instability is caused by impairment of replication fork progression
- 1College of Life Sciences, Peking University, Beijing 100871, China;
- 2National Institute of Biological Sciences, Beijing 102206, China;
- 3Obstetrics and Gynecology Department, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China;
- 4Department of Biological Sciences, Columbia University, New York, New York 10027, USA
Abstract
Transcriptional R loops are anomalous RNA:DNA hybrids that have been detected in organisms from bacteria to humans. These structures have been shown in eukaryotes to result in DNA damage and rearrangements; however, the mechanisms underlying these effects have remained largely unknown. To investigate this, we first show that R-loop formation induces chromosomal DNA rearrangements and recombination in Escherichia coli, just as it does in eukaryotes. More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stability. Strikingly, we found that attenuation of replication strongly suppresses R-loop-mediated DNA rearrangements in both E. coli and HeLa cells. Our findings thus provide a direct demonstration that R-loop formation impairs DNA replication and that this is responsible for the deleterious effects of R loops on genome stability from bacteria to humans.
Keywords
Footnotes
-
↵5 Corresponding author.
E-mail lixialu{at}nibs.ac.cn.
-
Supplemental material is available for this article.
-
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.17010011.
- Received May 10, 2011.
- Accepted August 22, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press