Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage
The hormone estrogen (E2) binds the estrogen receptor to promote transcription of E2-responsive genes in the breast and other tissues. E2 also has links to genomic instability, and elevated E2 levels are tied to breast cancer. Here, we show that E2 stimulation causes a rapid, global increase in the...
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| Vydáno v: | eLife Ročník 5 |
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| Hlavní autoři: | , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
England
eLife Science Publications, Ltd
23.08.2016
eLife Sciences Publications Ltd eLife Sciences Publications, Ltd |
| Témata: | |
| ISSN: | 2050-084X, 2050-084X |
| On-line přístup: | Získat plný text |
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| Shrnutí: | The hormone estrogen (E2) binds the estrogen receptor to promote transcription of E2-responsive genes in the breast and other tissues. E2 also has links to genomic instability, and elevated E2 levels are tied to breast cancer. Here, we show that E2 stimulation causes a rapid, global increase in the formation of R-loops, co-transcriptional RNA-DNA products, which in some instances have been linked to DNA damage. We show that E2-dependent R-loop formation and breast cancer rearrangements are highly enriched at E2-responsive genomic loci and that E2 induces DNA replication-dependent double-strand breaks (DSBs). Strikingly, many DSBs that accumulate in response to E2 are R-loop dependent. Thus, R-loops resulting from the E2 transcriptional response are a significant source of DNA damage. This work reveals a novel mechanism by which E2 stimulation leads to genomic instability and highlights how transcriptional programs play an important role in shaping the genomic landscape of DNA damage susceptibility.
The hormone estrogen controls the development of breast tissue. However too much estrogen can damage the DNA in human cells and may be linked to an increased risk of breast cancer. In breast cells, estrogen activates many genes via a process called transcription. The transcription process results in the production of an RNA molecule that contains a copy of the instructions encoded within the gene.
Previous studies have found that, in certain cases, a new RNA molecule can stick to the matching DNA from which it was made. This creates a structure known as an R-loop, which can lead the DNA to break. DNA breaks are particularly harmful because they can dramatically alter the cell’s genome in ways that allow it to become cancerous. However, it was not clear if the large increase in transcription triggered by estrogen causes an increase in R-loops, which could help to explain the DNA damage that has been reported to occur when cells are treated with estrogen.
Now, Stork et al. show that treating human breast cancer cells with estrogen causes an increase in R-loops and DNA breaks. The R-loops occurred particularly in regions of the genome that contain estrogen-activated genes. Stork et al. also found that regions of estrogen-activated transcription were more frequently mutated in breast cancers, and further experiments confirmed that the R-loops were responsible for many of the DNA breaks that occurred following estrogen treatment. Taken together, these findings demonstrate that the changes in transcription due to estrogen lead to increased R-loops and DNA breaks, which may make the cells vulnerable to becoming cancerous.
The next challenge is to determine precisely where these DNA breaks that result from estrogen occur on the DNA. Knowing the location of the DNA breaks will be useful in determining what additional factors or genomic features make an R-loop more prone to being broken. This in turn might help explain how the R-loops lead to DNA damage. In addition, further studies are also needed to determine if tumor samples from breast cancer patients also contain increased levels of R-loops. |
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| Bibliografie: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 |
| ISSN: | 2050-084X 2050-084X |
| DOI: | 10.7554/eLife.17548 |