R-loop-mediated genomic instability is caused by impairment of replication fork progression

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 investigat...

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Bibliographic Details
Published in:Genes & development 2011-10, Vol.25 (19), p.2041-2056
Main Authors: Gan, Wenjian, Guan, Zhishuang, Liu, Jie, Gui, Ting, Shen, Keng, Manley, James L, Li, Xialu
Format: Article
Language:English
Subjects:
Animals
DNA - chemistry
DNA Damage - genetics
DNA Replication - genetics
Escherichia coli
Escherichia coli - genetics
Evolution, Molecular
Gene Expression Regulation
Gene Rearrangement - genetics
Genomic Instability
HeLa Cells
Humans
Mice
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Nucleic Acid Conformation
Research Paper
Ribonuclease H - metabolism
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Serine-Arginine Splicing Factors
SOS Response (Genetics) - genetics
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.17010011