Classical non-homologous end-joining pathway utilizes nascent RNA for error-free double-strand break repair of transcribed genes

Chakraborty, Anirban; Tapryal, Nisha; Venkova, Tatiana; Horikoshi, Nobuo; Pandita, Raj K.; Sarker, Altaf H.; Sarkar, Partha S.; Pandita, Tej K.; Hazra, Tapas K.

doi:10.1038/ncomms13049

Cited by 153 publications

(224 citation statements)

References 49 publications

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“…12, 44 Again in yeast, an even more recent paper also demonstrates the formation of RNA:DNA hybrids at sites of DNA damage, showing a strong link between transcription and DNA repair. 45 Alternatively, they may also be involved in the process of modulating chromatin states, in a manner similar to piwi -interacting RNA in germ cells.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 98%

The emerging role of RNAs in DNA damage repair

Hawley

Wilczynska

et al. 2017

Cell Death Differ

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Many surveillance and repair mechanisms exist to maintain the integrity of our genome. All of the pathways described to date are controlled exclusively by proteins, which through their enzymatic activities identify breaks, propagate the damage signal, recruit further protein factors and ultimately resolve the break with little to no loss of genetic information. RNA is known to have an integral role in many cellular pathways, but, until very recently, was not considered to take part in the DNA repair process. Several reports demonstrated a conserved critical role for RNA-processing enzymes and RNA molecules in DNA repair, but the biogenesis of these damage-related RNAs and their mechanisms of action remain unknown. We will explore how these new findings challenge the idea of proteins being the sole participants in the response to DNA damage and reveal a new and exciting aspect of both DNA repair and RNA biology. Cell Death and Differentiation (2017) 24, 580-587; doi:10.1038/cdd.2017; published online 24 February 2017 FactsThe miRNA biogenesis machinery has a role in DNA damage repair outside of canonical miRNA-mediated translational repression. RNA molecules have been observed in the proximity of DNA breaks and have been implicated in the DNA repair response. These phenomena have been observed in many species, indicating an evolutionarily conserved mechanism. Open QuestionsWhat is the precise role of the RNA-processing enzymes in DNA repair? Do small RNAs have a direct mechanistic role in DNA repair, or do they serve as a by-product of a different RNA species? Is transcription induced locally at sites of DNA damage? Are proximal dormant promoter elements involved, or is an open-ended break sufficient for polymerase recruitment? Can these results be replicated outside of integrated exogenous reporter systems?An Unlikely Match: RNA Biogenesis Machinery Meets DNA Repair Our DNA is constantly exposed to various environmental and chemical agents, including ionising radiation (IR) from cosmic radiation, ultraviolet (UV) light from the sun or even nucleophilic attack induced by chemical compounds in food.1 In fact, DNA damage is intrinsic to the process of life: it is inevitable during replication and essential during meiotic recombination. Also, controlled DNA breaks by topoisomerase occur to facilitate the resolution of supercoiled chromatin structures.Complex mechanisms have evolved to counteract the variety and quantity of DNA damage encountered daily. Generally, DNA damage response (DDR) involves a complex signalling cascade initiated by one of three PI3K-like kinases: ATM, ATR or DNA-PK. They serve to facilitate chromatin modification and remodelling, allowing access to and acting as scaffolds for proteins involved in repair, as well as propagating the damage signal.1 Many of these recruited factors are involved in a binary decision-making process (see Figure 1). The repair of double-strand breaks (DSBs) is resolved by two distinct mechanisms: error-free homologous recombination (HR) or error-prone non-homologous ...

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Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 98%

The emerging role of RNAs in DNA damage repair

Hawley

Wilczynska

et al. 2017

Cell Death Differ

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“…Interestingly, Chakraborty et al recently showed that non-homologous end joining proteins preferentially associate with transcribed sequences following DSB induction and facilitate an error-free mechanism of DSB repair in transcribed DNA in mammalian cells (Chakraborty et al, 2016), supporting an RNA-guided DSB repair mechanism occurring prior to extensive end resection at the DSB ends. Here, we propose that Rad52 inverse RNA strand exchange can contribute to RNA-directed DSB repair in conditions of limited end resection by generating a heteroduplex between RNA and homologous DNA at the site of DSBs, in which RNA serves as a bridging template guiding DSB repair with or without a short gap filling synthesis (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Rad52 Inverse Strand Exchange Drives RNA-Templated DNA Double-Strand Break Repair

et al. 2017

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SUMMARY RNA can serve as a template for DNA double-strand break repair in yeast cells, and Rad52, a member of the homologous recombination pathway, emerged as an important player in this process. However, the exact mechanism of how Rad52 contributes to RNA-dependent DSB repair remained unknown. Here, we report an unanticipated activity of yeast and human Rad52: inverse strand exchange, in which Rad52 forms a complex with dsDNA and promotes strand exchange with homologous ssRNA or ssDNA. We show that in eukaryotes, inverse strand exchange between homologous dsDNA and RNA is a distinctive activity of Rad52; neither Rad51 recombinase nor the yeast Rad52 paralog Rad59 has this activity. In accord with our in vitro results, our experiments in budding yeast provide evidence that Rad52 inverse strand exchange plays an important role in RNA-templated DSB repair in vivo.

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“…The biological role of Rloops is currently under intense investigation. It was found that R-loops are essential for repair of DNA double-strand breaks in actively transcribed genome regions through TC-HR (Marnef et al, 2017;Wei et al, 2016;Yasuhara et al, 2018) or Non-Homologous End-Joining (Chakraborty et al, 2016). It was proposed by Kogoma that R-loops may serve as a primer to restart DNA replication stalled at DNA lesions (Kogoma, 1997) ( Figure 7).…”

Section: Rpa-rna Interactions In Vivomentioning

confidence: 99%

Replication protein A binds RNA and promotes R-loop formation

Mazina

Somarowthu

Kadyrova

et al. 2020

Preprint

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Replication protein A (RPA), a major eukaryotic ssDNA-binding protein, is essential for all metabolic processes that involve ssDNA including DNA replication, repair, and damage signaling. Surprisingly, we found here that RPA binds RNA in vitro with high affinity. Using native RIP method, we isolated RNA-RPA complexes from human cells.Furthermore, RPA promotes R-loop formation between RNA and homologous dsDNA.R-loops, the three-stranded nucleic acid structure consisting of an RNA-DNA hybrid and the displaced ssDNA strand, are common in human genome. R-loops may play an important role in transcription-coupled homologous recombination and DNA replication restart. We reconstituted the process of replication restart in vitro using RPA-generated R-loops and human DNA polymerases. These findings indicate that RPA may play a role in RNA metabolism and suggest a mechanism of genome maintenance that depends on RPA and RNA.

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Classical non-homologous end-joining pathway utilizes nascent RNA for error-free double-strand break repair of transcribed genes

Cited by 153 publications

References 49 publications

The emerging role of RNAs in DNA damage repair

The emerging role of RNAs in DNA damage repair

Rad52 Inverse Strand Exchange Drives RNA-Templated DNA Double-Strand Break Repair

Replication protein A binds RNA and promotes R-loop formation

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