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A role for RNA and DNA:RNA hybrids in the modulation of DNA repair by homologous recombination

Giuseppina D'Alessandro, Marek Adamowicz, Donna Whelan, Sean Michael Howard, Corey Winston Jones-Weinert, Valentina Matti, Eli Rothenberg, Petr Cejka, Fabrizio d'Adda di Fagagna

Preprint posted on January 29, 2018 https://www.biorxiv.org/content/early/2018/01/29/255976

RNA in unexpected places: dilncRNAs at resected DSB ends facilitate homologous recombination-mediated repair of broken DNA

Selected by Carmen Adriaens

 

RNA in unexpected places: dilncRNAs at resected DSB ends facilitate homologous recombination-mediated repair of broken DNA.

 

The idea: 

Upon double stranded DNA break (DSB) formation, non-coding RNAs at the resected ends of the break enhance BRCA1 recruitment and facilitate homologous recombination (HR) in the S and G2 phases of the cell cycle.

What is this preprint about?

Because of its potential mutagenic effect, DNA damage is one of the most dangerous insults for the cell. Although the protein component of the DNA repair machinery has been relatively well documented, recent work has also identified (non-coding) RNA as a major contributor to fine-tune the DNA repair pathways. In 2017, the group of Dr. Fabrizio d’Adda di Fagagna showed that in mammalian cells, a novel class of long non-coding RNAs (dilncRNAs) is transcribed from broken ends upon DSB formation after resection, a process necessary to free up DNA ends before HR can occur. They evidenced that these dilncRNAs contribute to the DNA repair process both by acting as precursors for DNA damage-associated small non-coding RNAs (DDRNA, previously characterized in Francia et al., 2012) and through the recruitment of DDRNAs by RNA-RNA pairing (see Michelini et al., NCB, 2017). In their recent preprint, the same authors show that dilncRNAs enhance HR-mediated DNA repair in the HR-prone S and G2 phases of the cell cycle by recruiting major HR factors. Moreover, they provide evidence that RNAse H2 is in a complex with the HR proteins BRCA1, PALB2, BRCA2 and RAD51, and that this R-loop-resolving protein is essential to remove the DNA-damage induced DNA-RNA hybrids so that proper repair can occur.

My opinion: 

What I love about this preprint is that this study helps to put forward the notion that RNA molecules play crucial roles in processes commonly considered to be dominated solely by a protein system.

Specifically, in the nucleus, ephemeral RNA molecules act not only as messengers, but also as guides, supports, protectors, inhibitors or physical barriers, recruiters, or flag signs. The dilncRNAs help generic and abundant proteins, such as those of the DNA repair machinery, to make the right choice in the right place and time. Because these RNAs are so versatile and short-lived, they provide the perfect “LINC” between a robust response to damage and an elegant fine-tuning of the complex nuclear environment.

In the future, it would be interesting to determine how the formation of RNA:DNA hybrids per se contributes to the DNA repair process, especially since they have been reported to be both the cause and consequence of DNA damage. Furthermore, it will be important to study to a further degree how the breaks and their repair are influenced by the RNA species (either bound or not to the broken and resected DNA ends), and how the proteins that regulate the biogenesis and metabolism of these RNA species affect the repair process.

Further reading: 

1. Transient RNA-DNA Hybrids Are Required for Efficient Double-Strand Break Repair. Ohle, Tesorero et al., 2016, Cell, Volume 167, Issue 4, 1001 – 1013.e7
This paper used a yeast system (S. pombe) to show how resected ends are transcribed bidirectionally and serve as substrates for DNA-RNA hybrid formation. It conceptually led the way for the current study.

2. Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks. Michelini et al., 2017, Nature Cell Biology 19, pages 1400–1411.
In this paper, the authors beautifully show a role for RNA polymerase II at DNA breaks and advance the idea that non-coding RNA may play a crucial role in DSB repair.

3. The emerging role of RNAs in DNA damage repair. Hawley et al., 2017. Cell death and differentiation. (2017) 24, 580–587
A great review on how in the last few years we came to realize how RNAs are more important than initially thought for the DNA repair processes in the cell.

4. Site-specific DICER and DROSHA RNA products control the DNA damage response. Francia et al. Nature (2012) 488(7410): 231–235.
The initial paper characterizing the involvement of DDRNA in the DNA repair process, through the DICER and DROSHA proteins, but not other components of the RNAi machinery.

 

Posted on bioRxiv Jan, 29th, 2018. doi: http://dx.doi.org/10.1101/255976

 

Tags: dilncrna, dna repair, dna:rna hybrid, homologous recombination, rnase h

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